Bicyclic heterocycles as fgfr inhibitors

ABSTRACT

The present invention relates to bicyclic heterocycles, and pharmaceutical compositions of the same, that are inhibitors of the FGFR enzyme and are useful in the treatment of FGFR-associated diseases such as cancer.

FIELD OF THE INVENTION

The present disclosure relates to bicyclic heterocycles, andpharmaceutical compositions of the same, that are inhibitors of theenzyme FGFR and are useful in the treatment of FGFR-associated diseasessuch as cancer.

BACKGROUND OF INVENTION

The Fibroblast Growth Factor Receptors (FGFR) are receptor tyrosinekinases that bind to fibroblast growth factor (FGF) ligands. There arefour FGFR proteins (FGFR1-4) that are capable of binding ligands and areinvolved in the regulation of many physiological processes includingtissue development, angiogenesis, wound healing, and metabolicregulation. Upon ligand binding, the receptors undergo dimerization andphosphorylation leading to stimulation of the protein kinase activityand recruitment of many intracellular docking proteins. Theseinteractions facilitate the activation of an array of intracellularsignaling pathways including Ras-MAPK, AKT-PI3K, and phospholipase Cthat are important for cellular growth, proliferation and survival(Reviewed in Eswarakumar et al. Cytokine & Growth Factor Reviews, 2005,16, 139-149). Aberrant activation of this pathway either throughoverexpression of FGF ligands or FGFR or activating mutations in theFGFRs can lead to tumor development, progression, and resistance toconventional cancer therapies. In human cancer, genetic alterationsincluding gene amplification, chromosomal translocations and somaticmutations that lead to ligand-independent receptor activation have beendescribed (Reviewed in Knights and Cook, Pharmacology & Therapeutics,2010, 125, 105-117; Turner and Grose, Nature Reviews Cancer, 2010, 10,116-129). Large scale DNA sequencing of thousands of tumor samples hasrevealed that FGFR genes are altered in many cancers (Helsten et al.Clin Cancer Res. 2016, 22, 259-267). Some of these activating mutationsare identical to germline mutations that lead to skeletal dysplasiasyndromes (Gallo et al. Cytokine & Growth Factor Reviews 2015, 26,425-449). Mechanisms that lead to aberrant ligand-dependent signaling inhuman disease include overexpression of FGFs and changes in FGFRsplicing that lead to receptors with more promiscuous ligand bindingabilities. Therefore, development of inhibitors targeting FGFR may beuseful in the clinical treatment of diseases that have elevated FGF orFGFR activity.

The cancer types in which FGF/FGFRs are implicated include, but are notlimited to: carcinomas (e.g., bladder, breast, colorectal, endometrial,gastric, head and neck, kidney, lung, ovarian, prostate); hematopoieticmalignancies (e.g., multiple myeloma, acute myelogenous leukemia, andmyeloproliferative neoplasms); and other neoplasms (e.g., glioblastomaand sarcomas). In addition to a role in oncogenic neoplasms, FGFRactivation has also been implicated in skeletal and chondrocytedisorders including, but not limited to, achrondroplasia andcraniosynostosis syndromes.

There is a continuing need for the development of new drugs for thetreatment of cancer, and the FGFR inhibitors described herein helpaddress this need.

SUMMARY OF INVENTION

The present disclosure is directed to compounds having Formula (I):

or pharmaceutically acceptable salts thereof, wherein constituentvariables are defined herein.

The present disclosure is further directed to pharmaceuticalcompositions comprising a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablecarrier.

The present disclosure is further directed to methods of inhibiting anFGFR enzyme (e.g., an FGFR3 enzyme) comprising contacting the enzymewith a compound of Formula (I), or a pharmaceutically acceptable saltthereof.

The present disclosure is further directed to a method of treating adisease associated with abnormal activity or expression of an FGFRenzyme (e.g., an FGFR3 enzyme), comprising administering a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, to a patientin need thereof.

The present disclosure is further directed to compounds of Formula (I)for use in treating a disease associated with abnormal activity orexpression of an FGFR enzyme (e.g., an FGFR3 enzyme).

The present disclosure is further directed to a method for treating adisorder mediated by an FGFR enzyme (e.g., an FGFR3 enzyme), or a mutantthereof, in a patient in need thereof, comprising the step ofadministering to said patient a compound of Formula (I), orpharmaceutically acceptable composition thereof.

The present disclosure is further directed to a method for treating adisorder mediated by an FGFR enzyme (e.g., an FGFR3 enzyme), or a mutantthereof, in a patient in need thereof, comprising the step ofadministering to the patient a compound of Formula (I), or apharmaceutically acceptable salt thereof, or a composition comprising acompound of Formula (I), or a pharmaceutically acceptable salt thereof,in combination with another therapy or therapeutic agent as describedherein.

Provided herein is also a method of treating cancer in a patient in needthereof comprising administering to the patient a therapeuticallyeffective amount of Formula I wherein the cancer is characterized by anFGFR2 and/or FGFR3 alteration.

The present disclosure is further directed to the use of compounds ofFormula (I) in the preparation of a medicament for use in therapy.

DETAILED DESCRIPTION Compounds

In one aspect, the present disclosure provides compounds of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

Cy¹ is selected from phenyl and 5-6 membered heteroaryl; wherein each5-6 membered heteroaryl has at least one ring-forming carbon atom and 1,2, or 3 ring-forming heteroatoms independently selected from N, O, andS; wherein the N and S are optionally oxidized; wherein a ring-formingcarbon atom of 5-6 membered heteroaryl is optionally substituted by oxoto form a carbonyl group; and wherein the phenyl and 5-6 memberedheteroaryl are each optionally substituted with 1, 2, 3 or 4substituents independently selected from R¹⁰;

R¹ is selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, 4-5 membered heterocycloalkyl, C₁₋₆ alkoxy,C₁₋₆ haloalkoxy, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkoxy,HO—C₁₋₃ alkoxy, HO—C₁₋₃ alkyl, cyano-C₁₋₃ alkyl, H₂N—C₁₋₃ alkyl, C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆alkylcarbonyl, and C₁₋₆ alkoxycarbonyl; wherein optionally one or more Hatoms of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₆ cycloalkyl, 4-5 membered heterocycloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkoxy, HO—C₁₋₃alkoxy, HO—C₁₋₃ alkyl, cyano-C₁₋₃ alkyl, H₂N—C₁₋₃ alkyl, C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆alkylcarbonyl, and C₁₋₆ alkoxycarbonyl are replaced by one or more Datoms;

each R² and R³ are independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ alkylene,4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene,5-10 membered heteroaryl-C₁₋₃ alkylene, halo, CN, NO₂, OR^(a2), SR^(a2),C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), C(═NR^(e2))R^(b2),C(═NOR^(a2))R^(b2), C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2),NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2),and S(O)₂NR^(c2)R^(d2); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R²¹;

or two adjacent R² substituents on the phenyl ring, taken together withthe atoms to which they are attached, form a fused 5- or 6-memberedcycloalkyl ring, or a fused 5- or 6-membered heterocycloalkyl ring;wherein each fused 5- or 6-membered heterocycloalkyl ring has at leastone ring-forming carbon atom and 1 or 2 ring-forming heteroatomsindependently selected from N, O, and S; wherein a ring-forming carbonatom of each fused 5- or 6-membered heterocycloalkyl ring is optionallysubstituted by oxo to form a carbonyl group; and wherein the fused 5- or6-membered cycloalkyl ring, and the fused 5- or 6-memberedheterocycloalkyl ring are each optionally substituted with 1, 2, 3 or 4substituents independently selected from R²¹;

n is selected from 0, 1, 2, and 3;

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-12 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ alkylene,4-12 membered heterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene,5-10 membered heteroaryl-C₁₋₃alkylene, halo, D, CN, NO₂, OR^(a1)SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1),OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), C(═NR^(e1))R^(b1),C(═NOR^(a1))R^(b1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),and S(O)₂NR^(c1)R^(d1); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-12 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-12 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ alkylene,4-10 membered heterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ alkylene, 5-10membered heteroaryl-C₁₋₃alkylene, halo, D, CN, OR^(a3), SR^(a3),C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), NR^(c3)R^(d3)NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3), NR^(c3)S(O)R^(b3),NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ alkylene,4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkyleneand 5-10 membered heteroaryl-C₁₋₃ alkylene are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹²;

each R¹² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR^(a5),SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), NR^(c5)R^(d5),NR^(c5)C(O)R^(b5), NR^(c5)C(O)OR^(a5), NR^(c5)S(O)R^(b5),NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), (O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl and 4-7 membered heterocycloalkyl, are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g);

each R²¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ alkylene,4-10 membered heterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene,5-10 membered heteroaryl-C₁₋₃ alkylene, halo, D, CN, OR^(a4), SR^(a4),C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), NR^(c4)R^(d4),NR^(c4)C(O)R^(b4) NR^(c4)C(O)OR^(a4), NR^(c4)S(O)R^(b4),NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ alkylene,4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkyleneand 5-10 membered heteroaryl-C₁₋₃ alkylene are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR²²;

each R²² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR^(a6),SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), NR^(c6)R^(d6)NR^(c6)C(O)R^(b6), NR^(c6)C(O)OR^(a6), NR^(c6)S(O)R^(b6),NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), and S(O)₂NR^(c6)R^(d6); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6membered heteroaryl and 4-7 membered heterocycloalkyl, are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g);

each R^(a1), R^(c1) and R^(d1) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl,are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹;

or any R^(c1) and R^(d1) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹;

each R^(b1) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹¹;

each R^(e1) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamoyl,di(C₁₋₆alkyl)carbamyl, amino sulfonyl, C₁₋₆ alkylaminosulfonyl anddi(C₁₋₆ alkyl)aminosulfonyl;

each R^(a2), R^(c2) and R^(d2), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²¹;

or any R^(c2) and R^(d2) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R²¹;

each R^(b2) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R²¹;

each R^(e2) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamoyl,di(C₁₋₆alkyl)carbamyl, amino sulfonyl, C₁₋₆ alkylaminosulfonyl anddi(C₁₋₆ alkyl)aminosulfonyl;

each R^(a3), R^(c3) and R^(d3), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl;wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹²;

or any R^(c3) and R^(d3) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R¹²;

each R^(b3) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkylC₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl, are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹²;

each R^(a4), R^(c4) and R^(d4), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl;wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²²;

or any R^(c4) and R^(d4) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R²²;

each R^(b4) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkylC₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR²²;

each R^(a5), R^(c5) and R^(d5), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g);

each R^(b5) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl C₂₋₆ alkenyland C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g);

each R^(a6), R^(c6) and R^(d6), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g);

each R^(b6) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyland C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g); and

each R^(g) is independently selected from OH, NO₂, CN, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₃₋₆cycloalkyl-C₁₋₂ alkylene, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₃ alkoxy-C₁₋₃alkyl, C₁₋₃ alkoxy-C₁₋₃ alkoxy, HO—C₁₋₃ alkoxy, HO—C₁₋₃ alkyl,cyano-C₁₋₃ alkyl, H₂N—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, di(C₁₋₆alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamoyl, di(C₁₋₆alkyl)carbamyl,carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino.

In one aspect, the present disclosure provides compounds of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

Cy¹ is selected from phenyl, pyridinyl and pyrazolyl; wherein the phenylpyridinyl and pyrazolyl are each optionally substituted with 1, 2, 3 or4 substituents independently selected from R¹⁰;

R¹ is selected from halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₅ cycloalkyl,4-5 membered heterocycloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₃alkoxy-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, C₁₋₆ alkylamino, anddi(C₁₋₆alkyl)amino; wherein any of the H atoms of the C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₅ cycloalkyl, 4-5 membered heterocycloalkyl, C₁₋₆ alkoxy,C₁₋₆ haloalkoxy, C₁₋₃ alkoxy-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, C₁₋₆ alkylamino,and di(C₁₋₆alkyl)amino can be replaced by D atoms;

each R² and R³ are independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl, halo,CN, OR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), NR^(c2)R^(d2),and S(O)₂R^(b2); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl,and 4-6 membered heterocycloalkyl are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R²¹;

or two adjacent R² substituents on the phenyl ring, taken together withthe atoms to which they are attached, form a fused 5- or 6-memberedcycloalkyl ring, or a fused 5- or 6-membered heterocycloalkyl ring;wherein each fused 5- or 6-membered heterocycloalkyl ring has at leastone ring-forming carbon atom and 1 or 2 ring-forming heteroatomsindependently selected from O and N; wherein a ring-forming carbon atomof each fused 5- or 6-membered heterocycloalkyl ring is optionallysubstituted by oxo to form a carbonyl group; and wherein the fused 5- or6-membered cycloalkyl ring, and the fused 5- or 6-memberedheterocycloalkyl ring are each optionally substituted with 1, 2, 3 or 4substituents independently selected from R²¹;

n is selected from 0 and 1;

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 4-12 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-12 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 memberedheteroaryl-C₁₋₃ alkylene, halo, D, CN, OR^(a1), C(O)R^(b1),(O)NR^(c1)R^(d1), C(O)OR^(a1); NR^(c1)R^(d1); NR^(c1)C(O)R^(b1), andS(O)₂R^(b1); wherein said C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-12 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ alkylene,4-12 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkyleneand 5-10 membered heteroaryl-C₁₋₃ alkylene are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, halo, D, CN, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3); NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3),S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3); wherein said C₁₋₆ alkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10membered heteroaryl, are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹²;

each R¹² is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆cycloalkyl, 4-7 membered heterocycloalkyl, halo, D, CN, OR^(a5),SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), NR^(c5)R^(d5),NR^(c5)C(O)R^(b5), S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5); wherein saidC₁₋₆ alkyl, C₃₋₆ cycloalkyl, and 4-7 membered heterocycloalkyl, are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g);

each R²¹ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, D, CN, OR^(a4), C(O)R^(b4), (O)NR^(c4)R^(d4), C(O))R^(a4),NR^(c4)R^(d4), and S(O)₂R^(b4); wherein said C₁₋₆ alkyl, is optionallysubstituted with 1, 2, or 3 substituents independently selected fromR²²;

each R²² is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, D, CN, OR^(a6), and NR^(c6)R^(d6); wherein said C₁₋₆ alkyl, isoptionally substituted with 1 or 2 substituents independently selectedfrom R^(g);

each R^(a1), R^(c1) and R^(d1) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, and 4-10 memberedheterocycloalkyl; wherein said C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, and 4-10membered heterocycloalkyl, are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹¹;

or any R^(c1) and R^(d1) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹;

each R^(b1) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, and 4-10 membered heterocycloalkyl, wherein said C₁₋₆alkyl, C₃₋₁₀ cycloalkyl, and 4-10 membered heterocycloalkyl, are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹¹;

each R^(a2), R^(b2) and R^(d2), is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, and 4-10 memberedheterocycloalkyl; wherein said C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, and 4-10membered heterocycloalkyl, are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R²¹;

or any R^(c2) and R^(d2) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, or 6-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R²¹;

each R^(b2) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, and 4-10 membered heterocycloalkyl; wherein said C₁₋₆alkyl, C₃₋₁₀ cycloalkyl, and 4-10 membered heterocycloalkyl, are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R²¹;

each R^(a3), R^(c3) and R^(d3), is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, and 4-7 memberedheterocycloalkyl; wherein said C₁₋₆ alkyl C₃₋₆ cycloalkyl, and 4-7membered heterocycloalkyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹²;

or any R^(c3) and R^(d3) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R¹²;

each R^(b3) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₆ cycloalkyl, and 4-7 membered heterocycloalkyl; wherein said C₁₋₆alkyl C₃₋₆ cycloalkyl, and 4-7 membered heterocycloalkyl, are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹²;

each R^(a4), R^(c4) and R^(d4), is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR²²;

each R^(b4) is independently selected from C₁₋₆ alkyl, and C₁₋₆haloalkyl; wherein said C₁₋₆ alkyl is optionally substituted with 1, 2,3, or 4 substituents independently selected from R²²;

each R^(a5), R^(c5) and R^(d5), is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, is optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR^(g);

each R^(b5) is independently selected from C₁₋₆ alkyl, and C₁₋₆haloalkyl; wherein said C₁₋₆ alkyl is optionally substituted with 1, 2,3, or 4 substituents independently selected from R^(g);

each R^(a6), R^(b6) and R^(d6), is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, is optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR^(g);

each R^(b6) is independently selected from C₁₋₆ alkyl, and C₁₋₆haloalkyl; wherein said C₁₋₆ alkyl, is optionally substituted with 1, 2,3, or 4 substituents independently selected from R^(g); and

each R^(g) is independently selected from OH, CN, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₃alkoxy-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, cyano-C₁₋₃ alkyl, H₂N—C₁₋₃ alkyl,amino, C₁₋₆ alkylamino, di(C₁₋₆alkyl)amino, C₁₋₆alkylthio,C₁₋₆alkylsulfonyl, carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, andC₁₋₆ alkylcarbonylamino.

In one aspect, the present disclosure provides compounds of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

Cy¹ is selected from phenyl, pyridine-3-yl and pyrazol-4-yl; wherein thephenyl, pyridine-3-yl and pyrazol-4-yl of Cy¹ are each optionallysubstituted with 1 substituent selected from R¹⁰;

R¹ is selected from Cl, C₁₋₃ alkyl, C₁₋₃ haloalkyl, cyclopropyl,azedinyl, hydroxymethyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy and C₁₋₃alkylamino; wherein the C₁₋₃ alkyl, C₁₋₃ haloalkyl, cyclopropyl,azedinyl, hydroxymethyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy and C₁₋₃alkylamino are each optionally substituted with 1, 2, 3, 4, 5, 6, or 7deuteriums;

each R² is independently selected from C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₃₋₆cycloalkyl, F, Cl, CN, and OR^(a2); wherein said C₁₋₃ alkyl, and C₃₋₆cycloalkyl, are each optionally substituted with 1, 2 or 3 substituentsindependently selected from R²¹;

or the R² substituents on the phenyl ring, taken together with the atomsto which they are attached, form a fused 5- or 6-membered cycloalkylring, or a fused 5- or 6-membered heterocycloalkyl ring; wherein eachfused 5- or 6-membered heterocycloalkyl ring has at least onering-forming carbon atom and 1 or 2 ring-forming O atoms; and whereinthe fused 5- or 6-membered cycloalkyl ring, and the fused 5- or6-membered heterocycloalkyl ring are each optionally substituted with 1or 2 substituents independently selected from R²¹;

n is 0;

each R¹⁰ is independently selected from C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₃₋₆cycloalkyl, 4-10 membered heterocycloalkyl, 5-6 membered heteroaryl,4-10 membered heterocycloalkyl-C₁₋₂ alkylene, 5-6 memberedheteroaryl-C₁₋₂alkylene, F, Cl, D, CN, OR^(a1), C(O)NR^(c1)R^(d1), andNR^(c1)R^(d1), wherein said C₁₋₃ alkyl, C₃₋₆ cycloalkyl, 4-10 memberedheterocycloalkyl, 5-6 membered heteroaryl, 4-10 memberedheterocycloalkyl-C₁₋₂ alkylene, and 5-6 membered heteroaryl-C₁₋₂alkylene are each optionally substituted with 1 or 2 substituentsindependently selected from R¹¹;

each R¹¹ is independently selected from C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₃₋₆cycloalkyl, 4-10 membered heterocycloalkyl, 5-6 membered heteroaryl, F,Cl, D, CN, OR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)S(O)₂R^(b3), S(O)₂R^(b3), andS(O)₂NR^(c3)R^(d3); wherein said C₁₋₃ alkyl, C₃₋₆ cycloalkyl, 4-10membered heterocycloalkyl, and 5-6 membered heteroaryl, are eachoptionally substituted with 1 or 2 substituents independently selectedfrom R¹²;

each R¹² is independently selected from C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₃₋₆cycloalkyl, 4-7 membered heterocycloalkyl, F, Cl, D, CN, OR^(a5),C(O)R^(b5), C(O)NR^(c5)R^(d5), and NR^(c5)R^(d5); wherein said C₁₋₃alkyl, C₃₋₆ cycloalkyl, and 4-7 membered heterocycloalkyl, are eachoptionally substituted with 1 substituent independently selected fromR^(g);

R²¹ is independently selected from C₁₋₃ alkyl, F, Cl, D, CN, andOR^(a4); wherein said C₁₋₃ alkyl, is optionally substituted with 1 or 2substituents independently selected from R²²;

each R²² is independently selected from F, Cl, D, CN, and OR^(a6);

each R^(a1), R^(c1) and R^(d1) is independently selected from H, C₁₋₃alkyl, C₁₋₃ haloalkyl, and 4-6 membered heterocycloalkyl; wherein saidC₁₋₃ alkyl, and 4-6 membered heterocycloalkyl, are each optionallysubstituted with 1 substituent independently selected from R¹¹;

each R^(a2) is independently selected from H, C₁₋₃ alkyl, and C₁₋₃haloalkyl;

each R^(a3), R^(c3) and R^(d3), is independently selected from H, C₁₋₃alkyl, C₁₋₃ haloalkyl, C₃₋₆ cycloalkyl, and 4-6 memberedheterocycloalkyl; wherein said C₁₋₃ alkyl C₃₋₆ cycloalkyl, and 4-6membered heterocycloalkyl are each optionally substituted with 1 or 2substituents independently selected from R¹²;

or any R^(c3) and R^(d3) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5- or 6-memberedheterocycloalkyl group optionally substituted with 1 or 2 substituentsindependently selected from R¹²;

each R^(b3) is independently selected from C₁₋₃ alkyl, C₁₋₃ haloalkyl,C₃₋₆ cycloalkyl, and 4-6 membered heterocycloalkyl; wherein said C₁₋₃alkyl C₃₋₆ cycloalkyl, and 4-6 membered heterocycloalkyl, are eachoptionally substituted with 1 or 2 substituents independently selectedfrom R¹²;

each R^(a4) is independently selected from H, C₁₋₃ alkyl, and C₁₋₃haloalkyl;

each R^(a5), R^(c5) and R^(d5), is independently selected from H, C₁₋₃alkyl, and C₁₋₃ haloalkyl; wherein said C₁₋₃ alkyl, is optionallysubstituted with 1 substituent independently selected from R^(g);

each R^(b5) is independently selected from C₁₋₃ alkyl, and C₁₋₃haloalkyl; wherein said C₁₋₃ alkyl is optionally substituted with 1substituents independently selected from R^(g);

each R^(a6) is independently selected from H, and C₁₋₃ alkyl; and

each R^(g) is independently selected from OH, CN, F, Cl, alkyl, and C₁₋₃haloalkyl.

In some embodiments, Cy¹ is selected from phenyl, pyridinyl andpyrazolyl; wherein the phenyl, pyridinyl, and pyrazolyl are eachoptionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹⁰. In some embodiments, Cy¹ is selected from phenyl,pyridinyl and pyrazolyl; wherein the phenyl, pyridinyl, and pyrazolylare each optionally substituted with 1 or 2 substituents independentlyselected from R¹⁰. In some embodiments, Cy¹ is selected from phenyl,pyridinyl and pyrazolyl; wherein the phenyl, pyridinyl, and pyrazolylare each optionally substituted with 1 substituent selected from R¹⁰. Insome embodiments, Cy¹ is selected from phenyl, pyridinyl and pyrazolyl;wherein the phenyl, pyridinyl, and pyrazolyl are each substituted with 1substituent selected from R¹⁰.

In some embodiments, Cy¹ is selected from phenyl, pyridin-3-yl andpyrazol-4-yl;

wherein the phenyl, pyridin-3-yl, and pyrazol-4-yl are each optionallysubstituted with 1 substituent selected from R¹⁰. In some embodiments,Cy¹ is selected from phenyl, pyridin-3-yl and pyrazol-4-yl; wherein thephenyl, pyridin-3-yl, and pyrazol-4-yl are each substituted with 1substituent selected from R¹⁰.

In some embodiments, Cy¹ is 5-6 membered heteroaryl optionallysubstituted with 1 or 2 substituents selected from R¹⁰. In someembodiments, Cy¹ is selected from pyridin-3-yl and pyrazol-4-yl; whereinthe pyridin-3-yl, and pyrazol-4-yl are each optionally substituted with1 substituent selected from R¹⁰.

In some embodiments, Cy¹ is pyrazol-4-yl optionally substituted with 1or 2 substituents selected from R¹⁰. In some embodiments, Cy¹ isselected from pyrazol-4-yl and pyridine-3-yl; wherein the pyrazol-4-yland pyridin-3-yl are each optionally substituted with 1 or 2substituents selected from R¹⁰. In some embodiments, Cy¹ is pyridin-3-yloptionally substituted with 1 or 2 substituents selected from R¹⁰. Insome embodiments, Cy¹ is phenyl optionally substituted with 1 or 2substituents selected from R¹⁰.

In some embodiments, R¹ is selected from halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₅ cycloalkyl, 4-5 membered heterocycloalkyl, C₁₋₆ alkoxy,C₁₋₆ haloalkoxy, C₁₋₃ alkoxy-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, C₁₋₆ alkylamino,and di(C₁₋₆ alkyl)amino; wherein optionally one or more H atoms of theC₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₅ cycloalkyl, 4-5 memberedheterocycloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₃ alkoxy-C₁₋₃ alkyl,HO—C₁₋₃ alkyl, C₁₋₆ alkylamino, and di(C₁₋₆ alkyl)amino are replaced byone or more D atoms.

In some embodiments, R¹ is selected from Cl, alkyl, C₁₋₃ haloalkyl,cyclopropyl, azetidinyl, hydroxymethyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy andC₁₋₃ alkylamino; wherein optionally one or more H atoms of the C₁₋₃alkyl, C₁₋₃ haloalkyl, cyclopropyl, azetidinyl, hydroxymethyl, C₁₋₃alkoxy, C₁₋₃ haloalkoxy and C₁₋₃ alkylamino are replaced by one or moreD atoms.

In some embodiments, R¹ is selected from Cl, C₁₋₂ alkyl, C₁₋₂ haloalkyl,cyclopropyl, hydroxymethyl, C₁₋₂ alkoxy, C₁₋₂ haloalkoxy and C₁₋₂alkylamino; wherein optionally one or more H atoms of the C₁₋₂ alkyl,C₁₋₂ haloalkyl, cyclopropyl, hydroxymethyl, C₁₋₂ alkoxy, C₁₋₂ haloalkoxyand C₁₋₂ alkylamino are replaced by D atoms.

In some embodiments, R¹ is selected from Cl, C₁₋₂ alkyl, C₁₋₂ haloalkyl,hydroxymethyl, C₁₋₂ alkoxy, C₁₋₂ haloalkoxy and C₁₋₂ alkylamino; whereinoptionally one or more H atoms of the C₁₋₂ alkyl, C₁₋₂ haloalkyl,hydroxymethyl, C₁₋₂ alkoxy, C₁₋₂ haloalkoxy and C₁₋₂ alkylamino arereplaced by one or more D atoms.

In some embodiments, R¹ is selected from Cl, CH₃, OCH₃, OCD₃, OCH₂CH₃,OCHF₂, NHCH₃, CHF₂, and CH₂OH.

In some embodiments, R¹ is C₁₋₂ alkoxy. In some embodiments, R¹ is OCH₃.In some embodiments, R¹ is OCD₃.

In some embodiments, each R² and R³ are independently selected from C₁₋₆alkyl, C₂₋₆ alkenyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, 4-6 memberedheterocycloalkyl, halo, CN, OR^(a2), (O)R^(b2), (O)NR^(c2)R^(d2),C(O)OR^(a2), NR^(c2)R^(d2), and S(O)₂R^(b2); wherein said C₁₋₆ alkyl,C₂₋₆ alkenyl, C₃₋₆ cycloalkyl, and 4-6 membered heterocycloalkyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²¹.

In some embodiments, each R² is independently selected from C₁₋₆ alkyl,C₁₋₃ haloalkyl, C₃₋₆ cycloalkyl, halo, CN, and OR^(a2); wherein saidC₁₋₆ alkyl and C₃₋₆ cycloalkyl are each optionally substituted with 1,2, 3, or 4 substituents independently selected from R²¹.

In some embodiments, each R² is independently selected from C₁₋₆ alkyl,C₃₋₆ cycloalkyl, halo, and OR^(a2); wherein said C₁₋₆ alkyl and C₃₋₆cycloalkyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R²¹.

In some embodiments, two adjacent R² substituents on the phenyl ring,taken together with the atoms to which they are attached, form a fused5- or 6-membered cycloalkyl ring, or a fused 5- or 6-memberedheterocycloalkyl ring; wherein each fused 5- or 6-memberedheterocycloalkyl ring has at least one ring-forming carbon atom and 1 or2 ring-forming heteroatoms independently selected from O and N; whereina ring-forming carbon atom of each fused 5- or 6-memberedheterocycloalkyl ring is optionally substituted by oxo to form acarbonyl group; and wherein the fused 5- or 6-membered cycloalkyl ring,and the fused 5- or 6-membered heterocycloalkyl ring are each optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR²¹.

In some embodiments, two adjacent R² substituents on the phenyl ring,taken together with the atoms to which they are attached, form a fused5-membered cycloalkyl ring, or a fused 5- or 6-membered heterocycloalkylring; wherein each fused 5- or 6-membered heterocycloalkyl ring has atleast one ring-forming carbon atom and 1 or 2 ring-forming O atoms; andwherein the fused 5-membered cycloalkyl ring, and the fused 5- or6-membered heterocycloalkyl ring are each optionally substituted with 1or 2 substituents independently selected from R²¹.

In some embodiments, each R² is independently selected from C₃₋₆cycloalkyl, C₁₋₂ alkyl, C₁₋₂ haloalkyl, F, Cl, CN, and OR^(a2); whereinsaid C₁₋₂ alkyl is optionally substituted with 1 substituent selectedfrom R²¹.

In some embodiments, each R² is independently selected from C₁₋₃ alkyl,C₁₋₃ haloalkyl, F, Cl, CN, and OR^(a2); wherein said C₁₋₆ alkyl isoptionally substituted with 1 substituent selected from R²¹.

In some embodiments, each R² is independently selected from C₁₋₂ alkyl,C₁₋₂ haloalkyl, F, Cl, CN, and OR^(a2); wherein said C₁₋₂ alkyl isoptionally substituted with 1 substituent selected from R²¹.

In some embodiments, each R² is independently selected from C₁₋₃ alkyl,C₁₋₃ haloalkyl, C₃₋₆ cycloalkyl, F, Cl, CN, and OR^(a2); wherein saidC₁₋₃ alkyl, and C₃₋₆ cycloalkyl, are each optionally substituted with 1,2 or 3 substituents independently selected from R²¹.

In some embodiments, each R² is independently selected from C₁₋₂ alkyland F; wherein said C₁₋₂ alkyl is optionally substituted with 1substituent selected from R²¹.

In some embodiments, each R² is independently selected from F, methyl,CH₂CN, and CD₃.

In some embodiments, each R² is independently selected from F, methyl,CH₂CN, cyclopropyl, and CD₃.

In some embodiments, each R² is independently selected from F, methyl,CH₂CN, CD₃, OH, OCH₃, and cyclopropyl.

In some embodiments, each R² is C₁₋₂ alkyl. In some embodiments, each R²is methyl.

In some embodiments, the R² substituents on the phenyl ring, takentogether with the atoms to which they are attached, form a fused5-membered cycloalkyl ring, or a fused 5-heterocycloalkyl ring; whereinthe fused 5-membered heterocycloalkyl ring has at least one ring-formingcarbon atom and 1 or 2 ring-forming O atoms; and wherein the fused5-membered cycloalkyl ring and the fused 5-membered heterocycloalkylring are each optionally substituted with 1 or 2 substituents selectedfrom R²¹.

In some embodiments, the R² substituents on the phenyl ring, takentogether with the atoms to which they are attached, form a fused 5- or6-membered cycloalkyl ring, or a fused 5- or 6-membered heterocycloalkylring; wherein each fused 5- or 6-membered heterocycloalkyl ring has atleast one ring-forming carbon atom and 1 or 2 ring-forming O atoms; andwherein the fused 5- or 6-membered cycloalkyl ring, or the fused 5- or6-membered heterocycloalkyl ring are each optionally substituted with 1substituent selected from R²¹

In some embodiments, the R² substituents, taken together with the atomsto which they are attached, form a fused cyclopentyl group or a fusedtetrahydrofuranyl group, each of which is optionally substituted with 1or 2 substituents selected from R²¹.

In some embodiments, the R² substituents, taken together with the atomsto which they are attached, form a fused cyclopentyl group, a fusedtetrahydrofuranyl group, a fused 1,4-dioxanyl group, or a fusedtetrahydropyranyl group, each of which is optionally substituted with 1or 2 substituents selected from R²¹.

In some embodiments, the R² substituents, taken together with the atomsto which they are attached, form a fused cyclopentyl group optionallysubstituted with 1 or 2 substituents independently selected from OH, CN,CH₂OH, and F.

In some embodiments, the R² substituents, taken together with the atomsto which they are attached, form a fused cyclopentyl group optionallysubstituted with 1 or 2 substituents independently selected from D, OH,CN, CH₂OH, and F.

In some embodiments, the R² substituents, taken together with the atomsto which they are attached, form a fused cyclopentyl group or a fusedcyclohexyl group; wherein the fused cyclopentyl group and the fusedcyclohexyl group have at least one ring-forming carbon atom and eachoptionally have 1 or 2 ring-forming O atoms; and wherein the fusedcyclopentyl group and the fused cyclohexly group are each optionallysubstituted with 1 or 2 substituents independently selected from D, OH,CN, CH₂OH, and F.

In some embodiments, the R² substituents, taken together with the atomsto which they are attached, form a fused cyclopentyl group.

In some embodiments, n is selected from 0 and 1.

In some embodiments, n is 0. In some embodiments, n is 1.

In some embodiments, each R¹⁰ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-12 membered heterocycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-12membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10membered heteroaryl-C₁₋₃ alkylene halo, D, CN, OR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), andS(O)₂R^(b1); wherein said C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-12 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-12 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹.

In some embodiments, each R¹⁰ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl, phenyl,5-6 membered heteroaryl, C₃₋₆ cycloalkyl-C₁₋₃alkylene, 4-6 memberedheterocycloalkyl-C₁₋₃alkylene, phenyl-C₁₋₃alkylene, 5-6 memberedheteroaryl-C₁₋₃ alkylene halo, D, CN, OR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), andS(O)₂R^(b1); wherein said C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 4-6 memberedheterocycloalkyl, phenyl, 5-6 membered heteroaryl, C₃₋₆cycloalkyl-C₁₋₃alkylene, 4-6 membered heterocycloalkyl-C₁₋₃alkylene,phenyl-C₁₋₃alkylene and 5-6 membered heteroaryl-C₁₋₃ alkylene are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹¹.

In some embodiments, each R¹⁰ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl, phenyl,5-6 membered heteroaryl, C₃₋₆ cycloalkyl-C₁₋₃alkylene, 4-6 memberedheterocycloalkyl-C₁₋₃alkylene, phenyl-C₁₋₃alkylene, 5-6 memberedheteroaryl-C₁₋₃ alkylene halo, D, CN, OR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), NR^(c1)R^(d1) NR^(c1)C(O)R^(b1), andS(O)₂R^(b1); wherein said C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 4-6 memberedheterocycloalkyl, phenyl, 5-6 membered heteroaryl, C₃₋₆cycloalkyl-C₁₋₃alkylene, 4-6 membered heterocycloalkyl-C₁₋₃alkylene,phenyl-C₁₋₃alkylene and 5-6 membered heteroaryl-C₁₋₃ alkylene are eachoptionally substituted with 1 or 2 substituents independently selectedfrom R¹¹.

In some embodiments, each R¹⁰ is independently selected from C₁₋₃ alkyl,C₁₋₃ haloalkyl, C₃₋₆ cycloalkyl, 4-10 membered heterocycloalkyl, 5-6membered heteroaryl, 4-6 membered heterocycloalkyl-C₁₋₂ alkylene, 5-6membered heteroaryl-C₁₋₂ alkylene, halo, D, CN, OR^(a1),C(O)NR^(c1)R^(d1), and NR^(cl)R^(d1); (wherein the C₁₋₃ alkyl, C₃₋₆cycloalkyl, 4-10 membered heterocycloalkyl, 5-6 membered heteroaryl, 4-6membered heterocycloalkyl-C₁₋₂ alkylene, and 5-6 memberedheteroaryl-C₁₋₂ alkylene are each optionally substituted with 1 or 2substituents independently selected from R¹¹.

In some embodiments, each R¹⁰ is independently selected from C₁₋₃ alkyl,C₁₋₃ haloalkyl, C₃₋₆ cycloalkyl, 4-10 membered heterocycloalkyl, 5-6membered heteroaryl, 4-6 membered heterocycloalkyl-C₁₋₂ alkylene, 5-6membered heteroaryl-C₁₋₂ alkylene, halo, D, CN, C(O)NR^(c1)R^(d1), andNR^(c1)R^(d1); wherein the C₁₋₃ alkyl, C₃₋₆ cycloalkyl, 4-10 memberedheterocycloalkyl, 5-6 membered heteroaryl, 4-6 memberedheterocycloalkyl-C₁₋₂ alkylene, and 5-6 membered heteroaryl-C₁₋₂alkylene are each optionally substituted with 1 or 2 substituentsindependently selected from R¹¹.

In some embodiments, each R¹⁰ is independently selected from C₁₋₃ alkyl,C₁₋₃ haloalkyl, OR^(a1), C₃₋₆ cycloalkyl, 4-10 memberedheterocycloalkyl, 5-6 membered heteroaryl, 4-6 memberedheterocycloalkyl-C₁₋₂ alkylene, 5-6 membered heteroaryl-C₁₋₂ alkylene,halo, D, CN, C(O)NR^(c1)R^(d1), and NR^(c1)R^(d1); wherein the C₁₋₃alkyl, C₃₋₆ cycloalkyl, 4-10 membered heterocycloalkyl, 5-6 memberedheteroaryl, 4-6 membered heterocycloalkyl-C₁₋₂ alkylene, and 5-6membered heteroaryl-C₁₋₂ alkylene are each optionally substituted with 1or 2 substituents independently selected from R¹¹.

In some embodiments, each R¹⁰ is independently selected from C₁₋₃ alkyl,C₁₋₃ haloalkyl, C₃₋₆ cycloalkyl, 4-10 membered heterocycloalkyl, 5-6membered heteroaryl, 4-6 membered heterocycloalkyl-C₁₋₂ alkylene, 5-6membered heteroaryl-C₁₋₂ alkylene, halo, D, CN, C(O)NR^(c1)R^(d1), andNR^(c1)R^(d1); wherein the C₁₋₃ alkyl, C₃₋₆ cycloalkyl, 4-10 memberedheterocycloalkyl, 5-6 membered heteroaryl, 4-6 memberedheterocycloalkyl-C₁₋₂ alkylene, and 5-6 membered heteroaryl-C₁₋₂alkylene are each optionally substituted with 1 substituent selectedfrom R¹¹, and optionally substituted with a second substituent selectedfrom C₁₋₂ alkyl.

In some embodiments, each R¹⁰ is independently selected from C₁₋₃ alkyl,C₁₋₃ haloalkyl, OR^(a1), C₃₋₆ cycloalkyl, 4-10 memberedheterocycloalkyl, 5-6 membered heteroaryl, 4-6 memberedheterocycloalkyl-C₁₋₂ alkylene, 5-6 membered heteroaryl-C₁₋₂ alkylene,halo, D, CN, C(O)NR^(c1)R^(d1), and NR^(c1)R^(d1); (wherein the C₁₋₃alkyl, C₃₋₆ cycloalkyl, 4-10 membered heterocycloalkyl, 5-6 memberedheteroaryl, 4-6 membered heterocycloalkyl-C₁₋₂ alkylene, and 5-6membered heteroaryl-C₁₋₂ alkylene are each optionally substituted with 1substituent selected from R¹¹, and optionally substituted with a secondsubstituent selected from C₁₋₂ alkyl.

In some embodiments, each R¹⁰ is independently selected from C₁₋₃ alkyl,C₁₋₃ haloalkyl, C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl, 5-6membered heteroaryl, 4-6 membered heterocycloalkyl-C₁₋₂ alkylene, 5-6membered heteroaryl-C₁₋₂ alkylene, halo, D, CN, C(O)NR^(c1)R^(d1), andNR^(c1)R^(d1); wherein the C₁₋₃ alkyl, C₃₋₆ cycloalkyl, 4-6 memberedheterocycloalkyl, 5-6 membered heteroaryl, 4-6 memberedheterocycloalkyl-C₁₋₂ alkylene, and 5-6 membered heteroaryl-C₁₋₂alkylene are each optionally substituted with 1 or 2 substituentsindependently selected from R¹¹.

In some embodiments, each R¹⁰ is independently selected from C₁₋₃ alkyl,C₁₋₃ haloalkyl, halo, D, CN, C(O)NR^(c1)R^(d1), and NR^(c1)R^(d1);wherein the C₁₋₃ alkyl is optionally substituted with 1 or 2substituents independently selected from R¹¹.

In some embodiments, each R¹⁰ is independently selected from C₃₋₆cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, 4-6membered heterocycloalkyl-C₁₋₂ alkylene, and 5-6 memberedheteroaryl-C₁₋₂ alkylene; wherein the C₃₋₆ cycloalkyl, 4-6 memberedheterocycloalkyl, 5-6 membered heteroaryl, 4-6 memberedheterocycloalkyl-C₁₋₂ alkylene, and 5-6 membered heteroaryl-C₁₋₂alkylene are each optionally substituted with 1 or 2 substituentsindependently selected from R¹¹.

In some embodiments, each R¹⁰ is independently selected from C₁₋₂ alkyl,C₁₋₂ haloalkyl, C₃₋₆ cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl,morpholinyl, piperazinyl, pyridinyl, piperazinonyl,diazabicyclo[2.2.1]heptanyl (morpholinyl)ethyl, (pyridinyl)methyl,(triazolyl)methyl, 1-oxa-3,8-diazaspiro[4.5]decan-2-one, F, Cl, D, CN,and NR^(c1)R^(d1); wherein the C₁₋₂ alkyl, C₃₋₆ cycloalkyl, C₃₋₆cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl,piperazinyl, pyridinyl, piperazinonyl, diazabicyclo[2.2.1]heptanyl(morpholinyl)ethyl, and (pyridinyl)methyl are each optionallysubstituted with 1 or 2 substituents independently selected from R¹¹.

In some embodiments, each R¹⁰ is independently selected from C₁₋₂ alkyl,C₃₋₆ cycloalkyl, halo, D, CN, OR^(a1), C(O)NR^(c1)R^(d1), NR^(c1)R^(d1),azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,pyridinyl, piperazinonyl, diazabicyclo[2.2.1]heptanyl(morpholinyl)ethyl, (pyridinyl)methyl, (triazolyl)methyl,thiomorpholinyl, 1-oxa-3,8-diazaspiro[4.5]decan-2-one, andhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl; wherein the C₁₋₂ alkyl, C₃₋₆cycloalkyl, C₃₋₆ cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl,morpholinyl, piperazinyl, pyridinyl, piperazinonyl,diazabicyclo[2.2.1]heptanyl (morpholinyl)ethyl, (pyridinyl)methyl,(triazolyl)methyl, thiomorpholinyl,1-oxa-3,8-diazaspiro[4.5]decan-2-one, andhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl are each optionally substitutedwith 1 or 2 substituents independently selected from R¹¹.

In some embodiments, each R¹⁰ is independently selected from C₁₋₂ alkyl,C₃₋₆ cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl,piperazinyl, pyridinyl, piperazinonyl, diazabicyclo[2.2.1]heptanyl(morpholinyl)ethyl, (pyridinyl)methyl, (triazolyl)methyl,thiomorpholinyl, 1-oxa-3,8-diazaspiro[4.5]decan-2-one, andhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, wherein the C₁₋₂ alkyl, C₃₋₆cycloalkyl, C₃₋₆ cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl,morpholinyl, piperazinyl, pyridinyl, piperazinonyl,diazabicyclo[2.2.1]heptanyl (morpholinyl)ethyl, (pyridinyl)methyl,(triazolyl)methyl, thiomorpholinyl,1-oxa-3,8-diazaspiro[4.5]decan-2-one, andhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl are each optionally substitutedwith 1 or 2 substituents independently selected from R¹¹

In some embodiments, when R¹⁰ is 4-10 membered heterocycloalkyl, aheteroatom of the heterocycloalkyl ring is substituted with R¹¹ withinacceptable valence. In some embodiments, when R¹⁰ is 4-6 memberedheterocycloalkyl, a heteroatom of the heterocycloalkyl ring issubstituted with R¹¹ within acceptable valence. In some embodiments, anS atom of the heterocycloalkyl ring is substituted with NR. In someembodiments, an S atom of the heterocycloalkyl ring is substituted withNR and O.

In some embodiments, each R¹⁰ is independently selected from C₁₋₂ alkyl,C₁₋₂ haloalkyl, F, Cl, D, CN, and NR^(c1)R^(d1); wherein the C₁₋₂ alkylis optionally substituted with 1 or 2 substituents independentlyselected from R¹¹.

In some embodiments, each R¹⁰ is independently selected from C₁₋₂ alkyl,C₁₋₂ haloalkyl, F, Cl, D, CN, OR^(a1), and NR^(c1)R^(d1); wherein theC₁₋₂ alkyl is optionally substituted with 1 or 2 substituentsindependently selected from R¹¹.

In some embodiments, each R¹⁰ is independently selected from C₃₋₆cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl,piperazinyl, pyridinyl, piperazinonyl, diazabicyclo[2.2.1]heptanyl(morpholinyl)ethyl, (pyridinyl)methyl, (triazinyl)methyl, and1-oxa-3,8-diazaspiro[4.5]decan-2-one; wherein the C₃₋₆ cycloalkyl, C₃₋₆cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl,piperazinyl, pyridinyl, piperazinonyl, diazabicyclo[2.2.1]heptanyl(morpholinyl)ethyl, and (pyridinyl)methyl are each optionallysubstituted with 1 or 2 substituents independently selected from R¹¹.

In some embodiments, each R¹⁰ is independently selected from C₁₋₂ alkyl,C₁₋₂ haloalkyl, C₃₋₆ cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl,morpholinyl, piperazinyl, pyridinyl, piperazinonyl,diazabicyclo[2.2.1]heptanyl (morpholinyl)ethyl, (pyridinyl)methyl,(triazinyl)methyl, 1-oxa-3,8-diazaspiro[4.5]decan-2-one, F, Cl, D, CN,NR^(c1)R^(d1); wherein the C₁₋₂ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl,azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,pyridinyl, piperazinonyl, diazabicyclo[2.2.1]heptanyl(morpholinyl)ethyl, and (pyridinyl)methyl are each optionallysubstituted with 1 substituent selected from R¹¹, and optionallysubstituted with a second substituent selected from C₁₋₂ alkyl.

In some embodiments, each R¹⁰ is independently selected from C₁₋₂ alkyl,C₃₋₆ cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl,piperazinyl, pyridinyl, piperazinonyl, diazabicyclo[2.2.1]heptanyl(morpholinyl)ethyl, (pyridinyl)methyl, (triazolyl)methyl, and1-oxa-3,8-diazaspiro[4.5]decan-2-one; wherein the C₁₋₂ alkyl, C₃₋₆cycloalkyl, C₃₋₆ cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl,morpholinyl, piperazinyl, pyridinyl, piperazinonyl,diazabicyclo[2.2.1]heptanyl (morpholinyl)ethyl, (pyridinyl)methyl and(triazolyl)methyl are each optionally substituted with 1 or 2substituents independently selected from R¹¹.

In some embodiments, each R¹⁰ is independently selected from C₁₋₂ alkyl,C₃₋₆ cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl,piperazinyl, pyridinyl, piperazinonyl, diazabicyclo[2.2.1]heptanyl(morpholinyl)ethyl, (pyridinyl)methyl, (triazolyl)methyl, and1-oxa-3,8-diazaspiro[4.5]decan-2-one; wherein the C₁₋₂ alkyl, C₃₋₆cycloalkyl, C₃₋₆ cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl,morpholinyl, piperazinyl, pyridinyl, piperazinonyl,diazabicyclo[2.2.1]heptanyl (morpholinyl)ethyl, (pyridinyl)methyl and(triazolyl)methyl are each optionally substituted with 1 substituentselected from R¹¹, and optionally substituted with a second substituentselected from C₁₋₂ alkyl.

In some embodiments, each R¹⁰ is independently selected from methyl,(1-methyl-1H-1,2,4-triazol-5-yl)methyl, pyrrolidin-3-yl,pyrrolidin-1-yl, 1-ethylpyrrolidin-3-yl, 1-methylazetidin-3-yl,1-ethylazetidin-3-yl, 4-acetylpiperazin-1-yl, 3-cyanocyclobutyl,1-(dimethylcarbamoyl)piperidin-4-yl, 1-(methoxycarbonyl)piperidin-4-yl,1-(methoxycarbonyl)azetidin-3-yl, 1-acetylazetidin-3-yl,1-(methylsulfonyl)azetidin-3-yl, 1-(dimethylcarbamoyl)azetidin-3-yl,1-(cyclopropanecarbonyl)azetidin-3-yl, pyridin-4-ylmethyl,2-morpholinoethyl, cyclopropyl, 2-cyanoethyl, 2-hydroxyethyl,pyridin-4-yl, 4-hydroxycyclohexyl, 4-methylpiperazin-1-yl,4-ethylpiperazin-1-yl, morpholino, 4-methyl-3-oxopiperazin-1-yl,4-hydroxypiperidin-1-yl, (R)-3,4-dimethylpiperazin-1-yl,(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl,4-(dimethylcarbamoyl)piperidin-1-yl, 4-carboxy-4-methylpiperidin-1-yl,(1 S,4 S)-4-acetamidocyclohexyl, 2,4-dimethylpiperazin-1-yl,4-(ethylcarbamoyl)piperazin-1-yl, 4-carbamoylpiperazin-1-yl,4-isopropylpiperazin-1-yl, 4-ethylpiperazin-1-yl,2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-8-yl, pyridin-2-ylmethyl,1-acetylpiperidin-4-yl), and 1-(methoxycarbonyl)piperidin-4-yl.

In some embodiments, each R¹⁰ is independently selected from methyl,(1-methyl-1H-1,2,4-triazol-5-yl)methyl, pyrrolidin-3-yl,pyrrolidin-1-yl, 1-ethylpyrrolidin-3-yl, 1-methylazetidin-3-yl,1-ethylazetidin-3-yl, 4-acetylpiperazin-1-yl, 3-cyanocyclobutyl,1-(dimethylcarbamoyl)piperidin-4-yl, 1-(methoxycarbonyl)piperidin-4-yl,1-(methoxycarbonyl)azetidin-3-yl, 1-acetylazetidin-3-yl,1-(methylsulfonyl)azetidin-3-yl, 1-(dimethylcarbamoyl)azetidin-3-yl,1-(cyclopropanecarbonyl)azetidin-3-yl, pyridin-4-ylmethyl,2-morpholinoethyl, cyclopropyl, 2-cyanoethyl, 2-hydroxyethyl,pyridin-4-yl, 4-hydroxycyclohexyl, 4-methylpiperazin-1-yl,4-ethylpiperazin-1-yl, morpholino, 4-methyl-3-oxopiperazin-1-yl,4-hydroxypiperidin-1-yl, (R)-3,4-dimethylpiperazin-1-yl,(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl,4-(dimethylcarbamoyl)piperidin-1-yl, 4-carboxy-4-methylpiperidin-1-yl,(1S,4S)-4-acetamidocyclohexyl, 2,4-dimethylpiperazin-1-yl,4-(ethylcarbamoyl)piperazin-1-yl, 4-carbamoylpiperazin-1-yl,4-isopropylpiperazin-1-yl, 4-ethylpiperazin-1-yl,2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-8-yl, pyridin-2-ylmethyl,1-acetylpiperidin-4-yl), 1-(methoxycarbonyl)piperidin-4-yl,(tetrahydrofuran-3-yl)oxy, 1-methyl-5-oxopyrrolidin-3-yl,1-(2-hydroxypropanoyl)piperidin-4-yl, 1-(2-hydroxyacetyl)piperidin-4-yl,4-carboxycyclohexyl, 3-amino-4-fluoropyrrolidin-1-yl,(7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl,(7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl,4-imino-4-oxo-4λ⁶-piperazin-1-yl,(2-hydroxy-N-methylacetamido)pyrrolidin-1-yl,4-(2-hydroxyethyl)piperazin-1-yl, 2-methoxyethoxy,(tetrahydro-2H-pyran-4-yl)oxy, cyclopropyl, and3-(2-hydroxy-N-methylacetamido)azetidin-1-yl.

In some embodiments, each R¹⁰ is independently selected from1-(2-hydroxyacetyl)pyrrolidin-3-yl, 1-acetylpiperidin-3-yl,1-(3′-pyrrolidin-2′-one)pyrrolidin-3-yl,1-(1′-methyl-(3′-pyrrolidin-2′-one))pyrrolidin-3-yl,1-(2-propanamide)pyrrolidin-3-yl, 1-(methyl-L-prolyl)piperidin-4-yl,1-(4-methylmorpholin-3-yl)pyrrolidin-3-yl, 3-cyanocyclobut-1-yl,1-(hydroxymethylcarbonyl)azetidin-3-yl,1-(2-(dimethylamino)ethanecarbonyl)azetidin-3-yl,1-(dimethylamino-methyl-acetyl)azetidin-3-yl,1-((1-methylazetidin-2-yl)carbonyl)azetidin-3-yl,1-(2-(4-methylpiperazin-1-yl)ethan-1-one)azetidin-3-yl,1-(2-(4-hydroxypiperazin-1-yl)ethan-1-one)azetidin-3-yl,1-((1-methylazetidin-2-yl)carbonyl)azetidin-3-yl,1-(hydroxy-methyl-acetyl)azetidin-3-yl,1-((trans)-3-hydroxycyclobutylcarbonyl)azetidin-3-yl,1-((cis)-3-hydroxycyclobutylcarbonyl)azetidin-3-yl,1-((4-methylmorpholin-3-yl)carbonyl)azetidin-3-yl,1-(hydroxyl-acetyl)pyrrolidin-3-yl,1-((tetrahydrofuran-2-yl)carbonyl)azetidin-3-yl,1-((tetrahydrofuran-3-yl)carbonyl)azetidin-3-yl,1-(hydroxy-methyl-acetyl)pyrrolidin-3-yl,1-(3-hydroxybutanoyl)azetidin-3-yl,1-((−3-hydroxy-3-methylcyclobutyl)carbonyl)azetidin-3-yl,1-(4-methylmorpholin-3-yl)carbonyl)pyrrolidin-3-yl,1-((hydroxymethyl)cyclobutylcarbonyl)azetidin-3-yl,1-((1-ethylazetidin-2-yl)carbonyl)azetidin-3-yl,1-((1-(2-fluoroethyl)azetidin-2-yl)carbonyl)azetidin-3-yl,1-((1-isopropylazetidin-2-yl)carbonyl)azetidin-3-yl,1-((1-(2-fluoroethyl)azetidin-2-yl)carbonyl)pyrrolidin-3-yl,1-((trans)-3-hydroxycyclobutylcarbonyl)pyrrolidin-3-yl,1-((cis)-3-hydroxycyclobutylcarbonyl)pyrrolidin-3-yl,1-((3-hydroxy-3-methylcyclobutyl)carbonyl)pyrrolidin-3-yl,1-(2-methoxyethan-1-one)azetidin-3-yl,1-(2-(dimethylamino)-2-methylpropan-1-one)azetidin-3-yl,1-((cyclopropane-1-carbonitrile)carbonyl)azetidin-3-yl,1-((ethan-1-ol)sulfonyl)azetidin-3-yl,1-((N,N-dimethylethan-1-amine)sulfonyl)azetidin-3-yl,1-((2-methoxyethyl)carboxylate)azetidin-3-yl,1-((3-methoxycyclobutyl)carbonyl)azetidin-3-yl,3-(2-hydroxy-N-methylacetamide)cyclopentyl,3-(2-hydroxypropanamid)cyclopentyl, 3-(2-hydroxyacetamide)cyclopentyl,3-(2-hydroxyethyl)-3-azabicyclo[3.1.0]hexan-1-yl,(4-hydroxypiperidin-1-yl)methyl,(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl, 1-(morpholin-4-yl)ethyl,(5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine-7-yl)methyl,1-(2-hydroxyethyl)piperidin-4-yl-4-carbonitrile,1-(2-hydroxyacetyl)piperidin-4-yl-4-carbonitrile,2-methoxyethylpiperazin-1-yl,1-(tetrahydro-2H-pyran-4-carbonyl)piperidin-4-yl-4-d,1-(2-methoxyacetyl)pyrrolidin-3-yl,1-(tetrahydrofuran-2-carbonyl)pyrrolidin-3-yl,3-(2-hydroxy-N-methylacetamide)azetidin-1-yl,1-((tetrahydrofuran-2-yl)carbonyl)azetidin-3-yl,1-((1-methylpiperidin-2-yl)carbonyl)azetidin-3-yl,1-(2-(dimethylamino)ethan-1-one)azetidin-3-yl,1-(3-hydroxypropan-1-one)azetidin-3-yl,1-(2-hydroxyethan-1-one)azetidin-3-yl,1-(2-hydroxypropan-1-one)azetidin-3-yl,1-(2-hydroxy-N-methylacetamide)cyclobut-3-yl,1-(2-hydroxyethan-1-one)-3-d-azetidin-3-yl, 1-carboxylatepiperidin-4-yl,1-(morpholine-4-carbonyl)piperidin-4-yl, 1-acetylpyrrolidin-3-yl,1-(morpholine-4-carbonyl)pyrrolidin-3-yl, cyanomethyl,1-propanenitrile-azetidin-3-yl,1-(2-methoxy-N-methylacetamide)cyclobut-3-yl,1-(3-hydroxy-N-methylpropanamide)cyclobut-3-yl,1-(2-hydroxy-N-methylpropanamide)cyclobut-3-yl,1-(2-hydroxyethan-1-one)azabicyclo[3.1.0]hexan-3-yl,1-((4-methylmorpholin-3-yl)carbonyl)azabicyclo[3.1.0]hexan-3-yl,1-(tetrahydro-2H-pyran-4-yl)azabicyclo[3.1.0]hexan-3-yl,1-(ethan-1-opazabicyclo[3.1.0]hexan-3-yl,1-(4-methylmorpholine-3-carbonyl)-3-carbonitrile-pyrrolidin-3-yl,1-(4-methylmorpholine-3-carbonyl)-4-carbonitrile-piperdin-4-yl,1-(2-hydroxyacetyl)-3-carbonitrile-pyrrolidin-3-yl,(1,3-dimethylpiperazin-4-yl-2-one)methyl, and(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl.

In some embodiments, each R¹⁰ is independently selected from methyl,(1-methyl-1H-1,2,4-triazol-5-yl)methyl, pyrrolidin-3-yl,pyrrolidin-1-yl, 1-ethylpyrrolidin-3-yl, 1-methylazetidin-3-yl,1-ethylazetidin-3-yl, 4-acetylpiperazin-1-yl, 3-cyanocyclobutyl,1-(dimethylcarbamoyl)piperidin-4-yl, 1-(methoxycarbonyl)piperidin-4-yl,1-(methoxycarbonyl)azetidin-3-yl, 1-acetylazetidin-3-yl,1-(methylsulfonyl)azetidin-3-yl, 1-(dimethylcarbamoyl)azetidin-3-yl,1-(cyclopropanecarbonyl)azetidin-3-yl, pyridin-4-ylmethyl,2-morpholinoethyl, cyclopropyl, 2-cyanoethyl, 2-hydroxyethyl,pyridin-4-yl, 4-hydroxycyclohexyl, 4-methylpiperazin-1-yl,4-ethylpiperazin-1-yl, morpholino, 4-methyl-3-oxopiperazin-1-yl,4-hydroxypiperidin-1-yl, (R)-3,4-dimethylpiperazin-1-yl,(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl,4-(dimethylcarbamoyl)piperidin-1-yl, 4-carboxy-4-methylpiperidin-1-yl,(1S,4S)-4-acetamidocyclohexyl, 2,4-dimethylpiperazin-1-yl,4-(ethylcarbamoyl)piperazin-1-yl, 4-carbamoylpiperazin-1-yl,4-isopropylpiperazin-1-yl, 4-ethylpiperazin-1-yl,2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-8-yl, pyridin-2-ylmethyl,1-acetylpiperidin-4-yl), 1-(methoxycarbonyl)piperidin-4-yl,(tetrahydrofuran-3-yl)oxy, 1-methyl-5-oxopyrrolidin-3-yl,1-(2-hydroxypropanoyl)piperidin-4-yl, 1-(2-hydroxyacetyl)piperidin-4-yl,4-carboxycyclohexyl, 3-amino-4-fluoropyrrolidin-1-yl,(7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl,(7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl,4-imino-4-oxo-4λ⁶-piperazin-1-yl,(2-hydroxy-N-methylacetamido)pyrrolidin-1-yl,4-(2-hydroxyethyl)piperazin-1-yl, 2-methoxyethoxy,(tetrahydro-2H-pyran-4-yl)oxy, cyclopropyl, and3-(2-hydroxy-N-methylacetamido)azetidin-1-yl,1-(2-hydroxyacetyl)pyrrolidin-3-yl, 1-acetylpiperidin-3-yl,1-(3′-pyrrolidin-2′-one)pyrrolidin-3-yl,1-(1′-methyl-(3′-pyrrolidin-2′-one))pyrrolidin-3-yl,1-(2-propanamide)pyrrolidin-3-yl, 1-(methyl-L-prolyl)piperidin-4-yl,1-(4-methylmorpholin-3-yl)pyrrolidin-3-yl, 3-cyanocyclobut-1-yl,1-(hydroxymethylcarbonyl)azetidin-3-yl,1-(2-(dimethylamino)ethanecarbonyl)azetidin-3-yl,1-(dimethylamino-methyl-acetyl)azetidin-3-yl,1-((1-methylazetidin-2-yl)carbonyl)azetidin-3-yl,1-(2-(4-methylpiperazin-1-yl)ethan-1-one)azetidin-3-yl,1-(2-(4-hydroxypiperazin-1-yl)ethan-1-one)azetidin-3-yl,1-((1-methylazetidin-2-yl)carbonyl)azetidin-3-yl,1-(hydroxy-methyl-1-((trans)-3-hydroxycyclobutylcarbonyl)azetidin-3-yl,1-((cis)-3-hydroxycyclobutylcarbonyl)azetidin-3-yl,1-((4-methylmorpholin-3-yl)carbonyl)azetidin-3-yl,1-(hydroxyl-acetyl)pyrrolidin-3-yl,1-((tetrahydrofuran-2-yl)carbonyl)azetidin-3-yl,1-((tetrahydrofuran-3-yl)carbonyl)azetidin-3-yl,1-(hydroxy-methyl-acetyl)pyrrolidin-3-yl,1-(3-hydroxybutanoyl)azetidin-3-yl,1-((−3-hydroxy-3-methylcyclobutyl)carbonyl)azetidin-3-yl,1-(4-methylmorpholin-3-yl)carbonyl)pyrrolidin-3-yl,1-((hydroxymethyl)cyclobutylcarbonyl)azetidin-3-yl,1-((1-ethylazetidin-2-yl)carbonyl)azetidin-3-yl,1-((1-(2-fluoroethyl)azetidin-2-yl)carbonyl)azetidin-3-yl,1-((1-isopropylazetidin-2-yl)carbonyl)azetidin-3-yl,1-((1-(2-fluoroethyl)azetidin-2-yl)carbonyl)pyrrolidin-3-yl,1-((trans)-3-hydroxycyclobutylcarbonyl)pyrrolidin-3-yl,1-((cis)-3-hydroxycyclobutylcarbonyl)pyrrolidin-3-yl,1-((3-hydroxy-3-methylcyclobutyl)carbonyl)pyrrolidin-3-yl,1-(2-methoxyethan-1-one)azetidin-3-yl,1-(2-(dimethylamino)-2-methylpropan-1-one)azetidin-3-yl,1-((cyclopropane-1-carbonitrile)carbonyl)azetidin-3-yl,1-((ethan-1-ol)sulfonyl)azetidin-3-yl, 1-((N,N-dimethylethan-1-amine)sulfonyl)azetidin-3-yl, 1-((2-methoxyethyl)carboxylate)azetidin-3-yl,1-((3-methoxycyclobutyl)carbonyl)azetidin-3-yl,3-(2-hydroxy-N-methylacetamide)cyclopentyl,3-(2-hydroxypropanamid)cyclopentyl, 3-(2-hydroxyacetamide)cyclopentyl,3-(2-hydroxyethyl)-3-azabicyclo[3.1.0]hexan-1-yl,(4-hydroxypiperidin-1-yl)methyl,(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl, 1-(morpholin-4-yl)ethyl,(5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine-7-yl)methyl,1-(2-hydroxyethyl)piperidin-4-yl-4-carbonitrile,1-(2-hydroxyacetyl)piperidin-4-yl-4-carbonitrile,2-methoxyethylpiperazin-1-yl,1-(tetrahydro-2H-pyran-4-carbonyl)piperidin-4-yl-4-d,1-(2-methoxyacetyl)pyrrolidin-3-yl,1-(tetrahydrofuran-2-carbonyl)pyrrolidin-3-yl,3-(2-hydroxy-N-methylacetamide)azetidin-1-yl,1-((tetrahydrofuran-2-yl)carbonyl)azetidin-3-yl,1-((1-methylpiperidin-2-yl)carbonyl)azetidin-3-yl,1-(2-(dimethylamino)ethan-1-one)azetidin-3-yl,1-(3-hydroxypropan-1-one)azetidin-3-yl,1-(2-hydroxyethan-1-one)azetidin-3-yl,1-(2-hydroxypropan-1-one)azetidin-3-yl,1-(2-hydroxy-N-methylacetamide)cyclobut-3-yl,1-(2-hydroxyethan-1-one)-3-d-azetidin-3-yl, 1-carboxylatepiperidin-4-yl,1-(morpholine-4-carbonyl)piperidin-4-yl, 1-acetylpyrrolidin-3-yl,1-(morpholine-4-carbonyl)pyrrolidin-3-yl, cyanomethyl,1-propanenitrile-azetidin-3-yl,1-(2-methoxy-N-methylacetamide)cyclobut-3-yl,1-(3-hydroxy-N-methylpropanamide)cyclobut-3-yl,1-(2-hydroxy-N-methylpropanamide)cyclobut-3-yl,1-(2-hydroxyethan-1-one)azabicyclo[3.1.0]hexan-3-yl,1-((4-methylmorpholin-3-yl)carbonyl)azabicyclo[3.1.0]hexan-3-yl,1-(tetrahydro-2H-pyran-4-yl)azabicyclo[3.1.0]hexan-3-yl,1-(ethan-1-ol)azabicyclo[3.1.0]hexan-3-yl,1-(4-methylmorpholine-3-carbonyl)-3-carbonitrile-pyrrolidin-3-yl,1-(4-methylmorpholine-3-carbonyl)-4-carbonitrile-piperdin-4-yl,1-(2-hydroxyacetyl)-3-carbonitrile-pyrrolidin-3-yl,(1,3-dimethylpiperazin-4-yl-2-one)methyl, and(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl.

In some embodiments, each R¹¹ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, halo, D, CN, OR^(a3), SR^(a3),C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), NR^(c3)R^(d3),NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3), NR^(c3)S(O)₂R^(b3),NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3); whereinsaid C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl, and 5-10 membered heteroaryl, are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R¹².

In some embodiments, each R¹¹ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl, 4-6 memberedheterocycloalkyl, halo, D, CN, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)S(O)R^(b3), NR^(c3)S(O)_(2R) ^(b3),NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)_(2R)^(b3), and S(O)₂NR^(c3)R^(d3); wherein said C₁₋₆ alkyl, C₃₋₆ cycloalkyl,5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from R¹².

In some embodiments, each R¹¹ is independently selected from C₁₋₃ alkyl,C₁₋₃ haloalkyl, C₃₋₄ cycloalkyl, 5-6 membered heteroaryl, 4-6 memberedheterocycloalkyl, halo, D, CN, OR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)OR^(a3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), and S(O)₂R^(b3); whereinsaid C₁₋₃ alkyl, C₃₋₄ cycloalkyl, 5-6 membered heteroaryl, and 4-6membered heterocycloalkyl are each optionally substituted with 1substituent selected from R¹².

In some embodiments, each R¹¹ is independently selected from C₁₋₃ alkyl,C₁₋₃ haloalkyl, C₃₋₄ cycloalkyl, 5-6 membered heteroaryl, 4-6 memberedheterocycloalkyl, halo, D, CN, OR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)OR^(a3), NR^(c3)R^(d3) NR^(c3)C(O)R^(b3), S(O)₂R^(b3); andNR^(c3)S(O)₂R^(b3) wherein said C₁₋₃ alkyl, C₃₋₄ cycloalkyl, 5-6membered heteroaryl, and 4-6 membered heterocycloalkyl are eachoptionally substituted with 1 substituent selected from R¹².

In some embodiments, each R¹¹ is independently selected from halo, C₁₋₂alkyl, CN, OR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), and S(O)₂R^(b3), wherein said C₁₋₂alkyl is optionally substituted with OR^(a5).

In some embodiments, each R¹¹ is independently selected from halo, C₁₋₂alkyl, CN, OR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), S(O)₂R^(b3),1-methyl-pyrrolidin-3-yl-2-one, pyrrolidin-3-yl-2-one, 2-propanamide,NR^(c3)S(O)₂R^(b3), D, and tetrahydropyran-4-yl, wherein said C₁₋₂ alkylis optionally substituted with OR^(a5).

In some embodiments, each R¹¹ is independently selected from C₁₋₃ alkyl,4-10 membered heterocycloalkyl, F, D, CN, OR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)S(O)₂R^(b3), and S(O)₂R^(b3); wherein said C₁₋₃ alkyl, and 4-10membered heterocycloalkyl, are each optionally substituted with 1 or 2substituents independently selected from R¹².

In some embodiments, each R¹¹ is independently selected from C₁₋₂ alkyl,C₁₋₂ haloalkyl, F, Cl, D, CN, OR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)OR^(a3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), and S(O)₂R^(b3).

In some embodiments, each R¹¹ is independently selected from C₁₋₂ alkyl,CN, OR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),NR^(c3)C(O)R^(b3), and S(O)₂R^(b3).

In some embodiments, each R¹¹ is independently selected from methyl,ethyl, isopropyl, CN, OH, oxo, (1-methyl-1H-1,2,4-triazol-5-yl)methyl,C(O)CH₃, C(O)N(CH₃)₂, C(O)NH₂, C(O)NHCH₂CH₃, C(O)OCH₃, C(O)OH,NHC(O)CH₃, S(O)₂CH₃, cyclopropanecarbonyl, pyridin-4-yl, pyridin-2-yl,and morpholino.

In some embodiments, each R¹¹ is independently selected from methyl,ethyl, isopropyl, CN, OH, oxo, (1-methyl-1H-1,2,4-triazol-5-yl)methyl,C(O)CH₃, C(O)N(CH₃)₂, C(O)NH₂, C(O)NHCH₂CH₃, C(O)OCH₃, C(O)OH,NHC(O)CH₃, S(O)₂CH₃, cyclopropanecarbonyl, pyridin-4-yl, pyridin-2-yl,morpholino, 2-hydroxypropanoyl, 2-hydroxyacetyl, 2-hydroxyethyl, F, NH₂,and N(CH₃)C(O)CH₂OH.

In some embodiments, each R¹¹ is independently selected from methyl,ethyl, isopropyl, CN, OH, D, oxo,(1-methyl-1H-1,2,4-triazol-5-yl)methyl, C(O)CH₃, C(O)N(CH₃)₂, C(O)NH₂,C(O)NHCH₂CH₃, C(O)OCH₃, C(O)OH, NHC(O)CH₃, S(O)₂CH₃,cyclopropanecarbonyl, pyridin-4-yl, pyridin-2-yl, and morpholino.

In some embodiments, each R¹¹ is independently selected from D, methyl,ethyl, isopropyl, CN, OH, oxo, (1-methyl-1H-1,2,4-triazol-5-yl)methyl,CH₂CH₂OH, C(O)CH₃, C(O)N(CH₃)₂, C(O)NH₂, C(O)NHCH₂CH₃,C(O)CH₂CH₂N(CH₃)₂, C(O)CH(CH₃)N(CH₃)₂, C(O)OCH₃, C(O)CH₂OH,CH(CH₃)C(O)NH₂, C(O)OH, NHC(O)CH₃, S(O)₂CH₃, cyclopropanecarbonyl,pyridin-4-yl, pyridin-2-yl, morpholino, 2-hydroxypropanoyl,2-hydroxyacetyl, 2-hydroxyethyl, F, NH₂, N(CH₃)C(O)CH₂OH,3′-pyrrolidin-2′-one, methyl-3′-pyrrolidin-2′-one, 1-methyl-prolyl,(4-methylmorpholin-3-yl)methyl-1-one,(1-methylazetidin-2-yl)methyl-1-one,2-(4-methylpiperazin-1-yl)ethyl-1-one,2-(4-hydroxypiperidin-1-yl)ethyl-1-one, 2-hydroxypropyl-1-one,(trans)-3-hydroxycyclobutyl)methyl-1-one,(cis)-3-hydroxycyclobutypmethyl-1-one,(4-methylmorpholin-3-yl)methyl-1-one,(tetrahydrofuran-2-yl)methyl-1-one, 2-hydroxypropyl-1-one,3-hydroxybutyl-1-one, 3-hydroxy-3-methylcyclobutyl)methyl-1-one,(hydroxymethyl)cyclobutyl)methyl-one,(1-ethylazetidin-2-yl)methyl-1-one,(2-fluoroethyl)azetidin-2-yl)methyl-1-one,(1-isopropylazetidin-2-yl)methyl-1-one, 2-methoxyethyl-1-one,2-(dimethylamino)-2-methylpropyl-1-one,(cyclopropane-1-carbonitrile)methyl-1-one, S(O)₂CH₂CH₂OH,S(O)₂CH₂CH₂N(CH₃)₂, 2-methoxyethyl-carboxyl, N-methylmethanesulfonamido,2-hydroxy-N-methylacetamido, 2-hydroxypropanamido,tetrahydro-2H-pyran-4-methyl-1-one, 2-methoxyacetyl,2-hydroxy-N-methylacetamido, tetrahydrofuran-2-methyl-1-one,(1-methylpiperidin-2-yl)methyl-1-one, 2-(dimethylamino)ethyl-1-one,3-hydroxypropyl-1-one, methoxymethyl-carboxyl, morpholine-4-carbonyl,propylnitrile, 2-methoxy-N-methylacetamido,3-hydroxy-N-methylpropanamido, 2-hydroxy-N-methylpropanamido,tetrahydro-2H-pyran-4-yl, and 1,3-dimethylpiperazinyl-2-one.

In some embodiments, each R¹² is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, halo, D, CN, OR^(a5), and NR^(c5)R^(d5); wherein saidC₁₋₆ alkyl is optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g).

In some embodiments, each R¹² is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, 4-7 membered heterocycloalkyl, halo, D,CN, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5),NR^(c5)R^(d5), NR^(c5)C(O)^(b5), S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5);wherein said C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and 4-7 memberedheterocycloalkyl, are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g).

In some embodiments, each R¹² is independently selected from C₁₋₃ alkyl,C₁₋₃ haloalkyl, C₃₋₆ cycloalkyl, 4-7 membered heterocycloalkyl, F, Cl,D, CN, OR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), and NR^(c5)R^(d5);wherein said C₁₋₃ alkyl, C₃₋₆ cycloalkyl, and 4-7 memberedheterocycloalkyl, are each optionally substituted with 1 substituentindependently selected from R^(g).

In some embodiments, each R¹² is independently selected from C₁₋₃ alkyl,halo, D, and OR^(a5).

In some embodiments, R¹² is methyl.

In some embodiments, R¹² is OH.

In some embodiments, each R²¹ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, halo, D, CN, OR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4),C(O)OR^(a4), NR^(c4)R^(d4), and S(O)₂R^(b4); wherein said C₁₋₆ alkyl isoptionally substituted with 1, 2, or 3 substituents independentlyselected from R²².

In some embodiments, each R²¹ is independently selected from C₁₋₃ alkyl,halo, D, CN, and OR^(a4); wherein said C₁₋₃ alkyl is optionallysubstituted with 1 or 2 substituents independently selected from R²².

In some embodiments, each R²¹ is independently selected from C₁₋₂ alkyl,F, Cl, D, CN, and OR^(a4); wherein said C₁₋₂ alkyl is optionallysubstituted with 1 substituent selected from R²².

In some embodiments, each R²¹ is independently selected from C₁₋₂ alkyl,halo, D, CN, and OR^(a4); wherein said C₁₋₃ alkyl is optionallysubstituted with 1 or 2 substituents independently selected from R²².

In some embodiments, each R²¹ is independently selected from C₁₋₃ alkyl,halo, D, CN, and OR^(a4); wherein said C₁₋₃ alkyl, is optionallysubstituted with 1 or 2 substituents independently selected from R²².

In some embodiments, each R²¹ is independently selected from C₁₋₃ alkyl,F, Cl, D, CN, and OR^(a4); wherein said C₁₋₃ alkyl, is optionallysubstituted with 1 or 2 substituents independently selected from R²². Insome embodiments, each R²¹ is independently selected from C₁₋₂ alkyl, F,D, CN, and OR^(a4); wherein said C₁₋₂ alkyl is optionally substitutedwith 1 substituent selected from R²².

In some embodiments, each R²¹ is independently selected from methyl, F,D, CN, and OH;

In some embodiments, each R²² is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, halo, D, CN, OR^(a6), and NR^(c6)R^(d6); wherein saidC₁₋₆ alkyl is optionally substituted with 1 or 2 substituentsindependently selected from R^(g).

In some embodiments, each R²² is independently selected from F, Cl, D,CN, and OR^(a6).

In some embodiments, each R²² is independently selected from halo, D,CN, and OR^(a6).

In some embodiments, each R²² is independently selected from F, Cl, CN,and OR^(a6).

In some embodiments, R²² is OR^(a6). In some embodiments, R²² is OH. Insome embodiments, each R²² is independently selected from F and Cl. Insome embodiments, R²² is CN.

In some embodiments, each R^(a1), R^(c1) and R^(d1) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, and 4-6membered heterocycloalkyl; wherein said C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and4-6 membered heterocycloalkyl, are each optionally substituted with 1,2, or 3 substituents independently selected from R¹¹.

In some embodiments, each R^(a1), R^(c1) and R^(d1) is independentlyselected from H and C₁₋₆ alkyl.

In some embodiments, each R^(a1), R^(c1) and R^(d1) is independentlyselected from H, C₁₋₆ alkyl, and 4-6 membered heterocycloalkyl.

In some embodiments, any R^(c1) and R^(d1) attached to the same N atom,together with the N atom to which they are attached, form a 4-, 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, or 3substituents independently selected from R¹¹.

In some embodiments, each R^(c1) and R^(d1) is independently selectedfrom H, C₁₋₃ alkyl, and

C₁₋₃ haloalkyl.

In some embodiments, R^(c1) and R^(d1) is independently selected from Hand C₁₋₂ alkyl.

In some embodiments, each R^(b1) is independently selected from C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, and 4-6 memberedheterocycloalkyl; wherein said C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and 4-6membered heterocycloalkyl, are each optionally substituted with 1, 2, or3 substituents independently selected from R¹¹. In some embodiments,each R^(b1) is independently selected from C₁₋₆ alkyl.

In some embodiments, each R^(a2), R^(c2) and R^(d2), is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, and 4-6membered heterocycloalkyl; wherein said C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and4-6 membered heterocycloalkyl, are each optionally substituted with 1,2, or 3 substituents independently selected from R²¹.

In some embodiments, each R^(a2), R^(c2) and R^(d2), is independentlyselected from H and C₁₋₆ alkyl.

In some embodiments, each R^(a2) is independently selected from H andC₁₋₃ alkyl.

In some embodiments, each R^(a2) is independently selected from H andC₁₋₂ alkyl.

In some embodiments, any R^(c2) and R^(d2) attached to the same N atom,together with the N atom to which they are attached, form a 4-, 5-, or6-membered heterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R²¹.

In some embodiments, each R^(b2) is independently selected from C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, and 4-6 memberedheterocycloalkyl; wherein said C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and 4-6membered heterocycloalkyl, are each optionally substituted with 1, 2, or3 substituents independently selected from R²¹.

In some embodiments, each R^(b2) is independently selected from C₁₋₆alkyl.

In some embodiments, each R^(a3), R^(c3) and R^(d3), is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, and C₃₋₆ cycloalkyl;wherein said C₁₋₆ alkyl and C₃₋₆ cycloalkyl, are each optionallysubstituted with 1 or 2 substituents independently selected from R¹².

In some embodiments, each R^(a3), R^(c3) and R^(d3), is independentlyselected from H, C₁₋₃ alkyl, C₁₋₃ haloalkyl, and C₃₋₅ cycloalkyl.

In some embodiments, each R^(a3), R^(c3) and R^(d3), is independentlyselected from H and C₁₋₂ alkyl.

In some embodiments, any R^(c3) and R^(d3) attached to the same N atom,together with the N atom to which they are attached, form a 4-, 5- or6-membered heterocycloalkyl group optionally substituted with 1 or 2substituents independently selected from R¹².

In some embodiments, each R^(b3) is independently selected from C₁₋₆alkyl, C₁₋₆ haloalkyl, and C₃₋₆ cycloalkyl; wherein said C₁₋₆ alkyl andC₃₋₆ cycloalkyl, are each optionally substituted with 1 or 2substituents independently selected from R¹².

In some embodiments, each R^(b3) is independently selected from C₁₋₃alkyl, C₁₋₃ haloalkyl, C₃₋₆ cycloalkyl, and 4-6 memberedheterocycloalkyl; wherein said C₁₋₃ alkyl C₃₋₆ cycloalkyl, and 4-6membered heterocycloalkyl, are each optionally substituted with 1 or 2substituents independently selected from R¹².

In some embodiments, each R^(b3) is independently selected from C₁₋₃alkyl and C₃₋₅ cycloalkyl.

In some embodiments, each R^(b3) is independently selected from C₁₋₂alkyl and cyclopropyl. In some embodiments, each R^(b3) is independentlyselected from C₁₋₂ alkyl.

In some embodiments, each R^(a4), R^(b4) and R^(d4), is independentlyselected from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkylis optionally substituted with 1 or 2 substituents independentlyselected from R²².

In some embodiments, each R^(a4), R^(b4) and R^(d4), is independentlyselected from H, C₁₋₃ alkyl, and C₁₋₃ haloalkyl; wherein said C₁₋₃ alkylis optionally substituted with 1 or 2 substituents independentlyselected from R²².

In some embodiments, each R^(a4) is independently selected from H andC₁₋₃ alkyl.

In some embodiments, R^(a4) is independently selected from H and C₁₋₂alkyl. In some embodiments, R^(a4) is H.

In some embodiments, each R^(b4) is independently selected from C₁₋₆alkyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl is optionallysubstituted with 1 or 2 substituents independently selected from R²². Insome embodiments, each R^(b4) is independently selected from C₁₋₆ alkyl.

In some embodiments, each R^(a5), R^(c5) and R^(d5), is independentlyselected from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkylis optionally substituted with 1 or 2 substituents independentlyselected from R^(g).

In some embodiments, R^(a5) is selected from H and C₁₋₃ alkyl.

In some embodiments, each R^(b5) is independently selected from C₁₋₆alkyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl is optionallysubstituted with 1 or 2 substituents independently selected from R^(g).

In some embodiments, each R^(a6), R^(b6) and R^(d6), is independentlyselected from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkylis optionally substituted with 1 or 2 substituents independentlyselected from R^(g).

In some embodiments, each R^(a6) is independently selected from H andC₁₋₃ alkyl.

In some embodiments, R^(a6) is independently selected from H and C₁₋₂alkyl.

In some embodiments, each R^(b6) is independently selected from C₁₋₆alkyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl is optionallysubstituted with 1 or 2 substituents independently selected from R^(g).In some embodiments, each R^(b6) is independently selected from C₁₋₆alkyl.

In some embodiments, each R^(g) is independently selected from OH, CN,halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, C₁₋₃ alkoxy-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, cyano-C₁₋₃ alkyl,H₂N—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino, C₁₋₆alkylthio, C₁₋₆ alkylsulfonyl, carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆alkoxycarbonyl, and C₁₋₆ alkylcarbonylamino.

In some embodiments, each R^(g) is independently selected from halo,C₁₋₆ alkyl, and C₁₋₆ haloalkyl.

In some embodiments, each R^(g) is independently selected from OH, CN,F, Cl, alkyl, and C₁₋₃ haloalkyl.

In some embodiments the compound of Formula I is a compound of FormulaIa:

or a pharmaceutically acceptable salt thereof; wherein Cy¹, R¹, and eachR² are as defined herein.

In some embodiments the compound of Formula I is a compound of FormulaIIa:

or a pharmaceutically acceptable salt thereof; wherein Cy¹, each R², R³,and n are as defined herein.

In some embodiments the compound of Formula I is a compound of Formula

or a pharmaceutically acceptable salt thereof, wherein Cy¹ and each R²are as defined herein.

In some embodiments the compound of Formula I is a compound of FormulaIIIa:

or a pharmaceutically acceptable salt thereof, wherein R¹, each R², andR¹⁰ are as defined herein.

In some embodiments the compound of Formula I is a compound of FormulaIIIb:

or a pharmaceutically acceptable salt thereof, wherein R¹, each R², andR¹⁰ are as defined herein.

In some embodiments the compound of Formula I is a compound of FormulaIIIc:

or a pharmaceutically acceptable salt thereof, wherein R¹, each R², andR¹⁰ are as defined herein.

In some embodiments the compound of Formula I is a compound of FormulaIVa:

or a pharmaceutically acceptable salt thereof, wherein Cy¹ and R¹ are asdefined herein.

In some embodiments the compound of Formula I is a compound of FormulaIVb:

or a pharmaceutically acceptable salt thereof, wherein Cy¹ is as definedherein.

In some embodiments the compound of Formula I is a compound of FormulaVa:

or a pharmaceutically acceptable salt thereof, wherein m is 0, 1 or 2;and wherein Cy¹, and R²¹ are as defined herein. In some embodiments, mis 0. In some embodiments, m is 1. In some embodiments, m is 2.

In some embodiments the compound of Formula I is a compound of FormulaVb:

or a pharmaceutically acceptable salt thereof, wherein Cy¹ and R¹ are asdefined herein.

In some embodiments the compound of Formula I is a compound of FormulaVc:

or a pharmaceutically acceptable salt thereof, wherein Cy¹ is as definedherein.

In some embodiments the compound of Formula I is a compound of FormulaVI:

or a pharmaceutically acceptable salt thereof, wherein Cy¹ and R¹ are asdefined herein.

In some embodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein:

Cy¹ is selected from phenyl, pyridinyl and pyrazolyl; wherein the phenylpyridinyl and pyrazolyl are each optionally substituted with 1, 2, 3 or4 substituents independently selected from R¹⁰;

R¹ is selected from halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₅ cycloalkyl,4-5 membered heterocycloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₃alkoxy-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, C₁₋₆ alkylamino, anddi(C₁₋₆alkyl)amino; wherein optionally one or more H atoms of the C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₅ cycloalkyl, 4-5 membered heterocycloalkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₃ alkoxy-C₁₋₃ alkyl, HO—C₁₋₃ alkyl,C₁₋₆alkylamino, and di(C₁₋₆alkyl)amino are replaced by one or more Datoms;

each R² and R³ are independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl, halo,CN, OR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), NR^(c2)R^(d2),and S(O)₂R^(b2); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl,and 4-6 membered heterocycloalkyl are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R²¹;

or two adjacent R² substituents on the phenyl ring, taken together withthe atoms to which they are attached, form a fused 5- or 6-memberedcycloalkyl ring, or a fused 5- or 6-membered heterocycloalkyl ring;wherein each fused 5- or 6-membered heterocycloalkyl ring has at leastone ring-forming carbon atom and 1 or 2 ring-forming heteroatomsindependently selected from O and N; wherein a ring-forming carbon atomof each fused 5- or 6-membered heterocycloalkyl ring is optionallysubstituted by oxo to form a carbonyl group; and wherein the fused 5- or6-membered cycloalkyl ring, and the fused 5- or 6-memberedheterocycloalkyl ring are each optionally substituted with 1, 2, 3 or 4substituents independently selected from R²¹;

n is selected from 0 and 1;

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 4-12 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-12 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 memberedheteroaryl-C₁₋₃ alkylene, halo, D, CN, OR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), NR^(c1)R^(d1), NR^(c1)C(O)R¹, andS(O)₂R^(b1); wherein said C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-12 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-12 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl,halo, D, CN, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)OR^(a3), NR^(c3)R^(d3) NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3),NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3),S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3);wherein said C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl, and4-6 membered heterocycloalkyl are each optionally substituted with 1, 2,or 3 substituents independently selected from R¹²;

each R¹² is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, D, CN, OR^(a5), and NR^(c5)R^(d5); wherein said C₁₋₆ alkyl isoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g);

each R²¹ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, D, CN, OR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4),NR^(c4)R^(d4) and S(O)₂R^(b4); wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, or 3 substituents independently selected fromR²²;

each R²² is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, D, CN, OR^(a6), and NR^(c6)R^(d6); wherein said C₁₋₆ alkyl isoptionally substituted with 1 or 2 substituents independently selectedfrom R^(g);

each R^(a1), R^(c1) and R^(d1) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, and 4-6 memberedheterocycloalkyl; wherein said C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and 4-6membered heterocycloalkyl, are each optionally substituted with 1, 2, or3 substituents independently selected from R¹¹;

or any R^(c1) and R^(d1) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3substituents independently selected from R¹¹;

each R^(b1) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₆ cycloalkyl, and 4-6 membered heterocycloalkyl; wherein said C₁₋₆alkyl, C₃₋₆ cycloalkyl, and 4-6 membered heterocycloalkyl, are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from R¹¹;

each R^(a2), R^(c2) and R^(d2), is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, and 4-6 memberedheterocycloalkyl; wherein said C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and 4-6membered heterocycloalkyl, are each optionally substituted with 1, 2, or3 substituents independently selected from R²¹;

or any R^(c2) and R^(d2) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, or 6-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R²¹;

each R^(b2) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₆ cycloalkyl, and 4-6 membered heterocycloalkyl; wherein said C₁₋₆alkyl, C₃₋₆ cycloalkyl, and 4-6 membered heterocycloalkyl, are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from R²¹;

each R^(a3), R^(c3) and R^(d3), is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, and C₃-6 cycloalkyl; wherein said C₁₋₆ alkyl andC₃₋₆ cycloalkyl, are each optionally substituted with 1 or 2substituents independently selected from R¹²;

each R^(b3) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,and C₃₋₆ cycloalkyl; wherein said C₁₋₆ alkyl and C₃₋₆ cycloalkyl, areeach optionally substituted with 1 or 2 substituents independentlyselected from R¹²;

each R^(a4), R^(c4) and R^(d4), is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl is optionallysubstituted with 1 or 2 substituents independently selected from R²²;

each R^(b4) is independently selected from C₁₋₆ alkyl, and C₁₋₆haloalkyl; wherein said C₁₋₆ alkyl is optionally substituted with 1 or 2substituents independently selected from R²²;

each R^(a5), R^(c3) and R^(d5), is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl is optionallysubstituted with 1 or 2 substituents independently selected from R^(g);

each R^(a6), R^(b6) and R^(d6), is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl is optionallysubstituted with 1 or 2 substituents independently selected from R^(g);

and

each R^(g) is independently selected from OH, CN, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₃alkoxy-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, cyano-C₁₋₃ alkyl, H₂N—C₁₋₃ alkyl,amino, C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino, C₁₋₆ alkylthio, C₁₋₆alkylsulfonyl, carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, andC₁₋₆ alkylcarbonylamino.

In some embodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein:

Cy¹ is selected from phenyl, pyridin-3-yl and pyrazol-4-yl; wherein thephenyl, pyridin-3-yl and pyrazol-4-yl of Cy¹ are each optionallysubstituted with 1 substituent selected from R¹⁰;

R¹ is selected from Cl, C₁₋₃ alkyl, C₁₋₃ haloalkyl, cyclopropyl,azetidinyl, hydroxymethyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy and C₁₋₃alkylamino; wherein optionally one or more H atoms of the C₁₋₃ alkyl,C₁₋₃ haloalkyl, cyclopropyl, azetidinyl, hydroxymethyl, C₁₋₃ alkoxy,C₁₋₃ haloalkoxy and C₁₋₃ alkylamino are replaced by one or more D atoms;

each R² is independently selected from C₁₋₃ alkyl, C₁₋₃ haloalkyl, F,Cl, CN, and OR^(a2); wherein said C₁₋₆ alkyl is optionally substitutedwith 1 substituent selected from R²¹;

or the R² substituents on the phenyl ring, taken together with the atomsto which they are attached, form a fused 5- or 6-membered cycloalkylring, or a fused 5- or 6-membered heterocycloalkyl ring; wherein eachfused 5- or 6-membered heterocycloalkyl ring has at least onering-forming carbon atom and 1 or 2 ring-forming O atoms; and whereinthe fused 5- or 6-membered cycloalkyl ring, or the fused 5- or6-membered heterocycloalkyl ring are each optionally substituted with 1substituent selected from R²¹;

n is 0;

R¹⁰ is independently selected from C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₃₋₆cycloalkyl, 4-10 membered heterocycloalkyl, 5-6 membered heteroaryl, 4-6membered heterocycloalkyl-C₁₋₂ alkylene, 5-6 membered heteroaryl-C₁₋₂alkylene, halo, D, CN, C(O)NR^(c1)R^(d1); and NR^(c1)R^(d1); wherein thealkyl, C₃₋₆ cycloalkyl, 4-10 membered heterocycloalkyl, 5-6 memberedheteroaryl, 4-6 membered heterocycloalkyl-C₁₋₂ alkylene, and 5-6membered heteroaryl-C₁₋₂ alkylene are each optionally substituted with 1or 2 substituents independently selected from R¹¹;

each R¹¹ is independently selected from C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₃₋₄cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl,halo, D, CN, OR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),NR^(c3)R^(d3), NR^(c3)C(O)OR^(b3), and S(O)₂R^(b3); wherein the C₁₋₃alkyl, C₃₋₄ cycloalkyl, 5-6 membered heteroaryl, and 4-6 memberedheterocycloalkyl are each optionally substituted with 1 substituentselected from R¹²;

each R¹² is selected from alkyl, halo, D, and OR^(a5);

each R²¹ is independently selected from C₁₋₃ alkyl, halo, D, CN, andOR^(a4); wherein said C₁₋₃ alkyl, is optionally substituted with 1 or 2substituents independently selected from R²²;

each R²² is independently selected from halo, D, CN, and OR^(a6);

R^(c1) and R^(d1) are independently selected from H, C₁₋₃ alkyl, andC₁₋₃ haloalkyl;

each R^(a2) is independently selected from H and alkyl;

each R^(a3), R^(c3) and R^(d3), is independently selected from H, C₁₋₃alkyl, C₁₋₃ haloalkyl, and C₃₋₅ cycloalkyl;

each R^(b3) is independently selected from C₁₋₃ alkyl and C₃₋₅cycloalkyl;

each R^(a4) is independently selected from H and alkyl;

each R^(a5) is selected from H and C₁₋₃ alkyl; and

each R^(ab) is independently selected from H and C₁₋₃ alkyl.

In some embodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein:

Cy¹ is selected from phenyl, pyridin-3-yl and pyrazol-4-yl; wherein thephenyl, pyridin-3-yl and pyrazol-4-yl of Cy¹ are each optionallysubstituted with 1 substituent selected from R¹⁰;

R¹ is selected from Cl, C₁₋₃ alkyl, C₁₋₃ haloalkyl, cyclopropyl,azetidinyl, hydroxymethyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy and C₁₋₃alkylamino; wherein optionally one or more H atoms of the C₁₋₃ alkyl,C₁₋₃ haloalkyl, cyclopropyl, azetidinyl, hydroxymethyl, C₁₋₃ alkoxy,C₁₋₃ haloalkoxy and C₁₋₃ alkylamino are replaced by one or more D atoms;

each R² is independently selected from C₁₋₃ alkyl, C₁₋₃ haloalkyl, F,Cl, CN, and OR^(a2); wherein said C₁₋₆ alkyl is optionally substitutedwith 1 substituent selected from R²¹;

or the R² substituents on the phenyl ring, taken together with the atomsto which they are attached, form a fused 5- or 6-membered cycloalkylring, or a fused 5- or 6-membered heterocycloalkyl ring; wherein eachfused 5- or 6-membered heterocycloalkyl ring has at least onering-forming carbon atom and 1 or 2 ring-forming O atoms; and whereinthe fused 5- or 6-membered cycloalkyl ring, or the fused 5- or6-membered heterocycloalkyl ring are each optionally substituted with 1substituent selected from R²¹;

n is 0;

R¹⁰ is independently selected from C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₃₋₆cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, 4-6membered heterocycloalkyl-C₁₋₂ alkylene, 5-6 membered heteroaryl-C₁₋₂alkylene, halo, D, CN, C(O)NR^(c1)R^(d1); and NR^(c1)R^(d1); wherein thealkyl, C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 memberedheteroaryl, 4-6 membered heterocycloalkyl-C₁₋₂ alkylene, and 5-6membered heteroaryl-C₁₋₂ alkylene are each optionally substituted with 1or 2 substituents independently selected from R¹¹;

each R¹¹ is independently selected from C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₃₋₄cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl,halo, D, CN, OR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), and S(O)₂R^(b3); wherein the C₁₋₃alkyl, C₃₋₄ cycloalkyl, 5-6 membered heteroaryl, and 4-6 memberedheterocycloalkyl are each optionally substituted with 1 substituentselected from R¹²;

each R¹² is selected from alkyl, halo, D, and OR^(a5);

each R²¹ is independently selected from C₁₋₃ alkyl, halo, D, CN, andOR^(a4); wherein said C₁₋₃ alkyl, is optionally substituted with 1 or 2substituents independently selected from R²²;

each R²² is independently selected from halo, D, CN, and OR^(a6);

R^(c1) and R^(d1) are independently selected from H, C₁₋₃ alkyl, andC₁₋₃ haloalkyl;

each R^(a2) is independently selected from H and C₁₋₃ alkyl;

each R^(a3), R^(c3) and R^(d3), is independently selected from H, C₁₋₃alkyl, C₁₋₃ haloalkyl, and C₃₋₅ cycloalkyl;

each R^(b3) is independently selected from C₁₋₃ alkyl and C₃₋₅cycloalkyl;

each R^(a4) is independently selected from H and C₁₋₃ alkyl;

each R^(a5) is selected from H and C₁₋₃ alkyl; and

each R^(a6) is independently selected from H and C₁₋₃ alkyl.

In some embodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein:

Cy¹ is selected from phenyl, pyridin-3-yl and pyrazol-4-yl; wherein thephenyl, pyridin-3-yl and pyrazol-4-yl of Cy¹ are each optionallysubstituted with 1 substituent selected from R¹⁰;

R¹ is selected from Cl, C₁₋₂ alkyl, C₁₋₂ haloalkyl, cyclopropyl,hydroxymethyl, C₁₋₂ alkoxy, C₁₋₂ haloalkoxy and C₁₋₂ alkylamino; whereinoptionally one or more H atoms of the C₁₋₂ alkyl, C₁₋₂ haloalkyl,cyclopropyl, hydroxymethyl, C₁₋₂ alkoxy, C₁₋₂ haloalkoxy and C₁₋₂alkylamino are replaced by one or more D atoms;

each R² is independently selected from C₁₋₂ alkyl, C₁₋₂ haloalkyl, F,Cl, CN, and OR^(a2); wherein said C₁₋₂ alkyl is optionally substitutedwith 1 substituent selected from R²¹;

or the R² substituents on the phenyl ring, taken together with the atomsto which they are attached, form a fused 5- or 6-membered cycloalkylring, or a fused 5- or 6-membered heterocycloalkyl ring; wherein eachfused 5- or 6-membered heterocycloalkyl ring has at least onering-forming carbon atom and 1 or 2 ring-forming O atoms; and whereinthe fused 5- or 6-membered cycloalkyl ring, or the fused 5- or6-membered heterocycloalkyl ring are each optionally substituted with 1substituent selected from R²¹;

n is 0;

R¹⁰ is independently selected from C₁₋₂ alkyl, C₁₋₂ haloalkyl, C₃₋₆cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl,piperazinyl, pyridinyl, piperazinonyl, diazabicyclo[2.2.1]heptanyl,(morpholinyl)ethyl, (pyridinyl)methyl, (triazolyl)methyl,1-oxa-3,8-diazaspiro[4.5]decan-2-one, F, Cl, D, CN, NR^(c1)R^(d1);wherein the C₁₋₂ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl, azetidinyl,pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyridinyl,piperazinonyl, diazabicyclo[2.2.1]heptanyl (morpholinyl)ethyl,(pyridinyl)methyl and (triazolyl)methyl are each optionally substitutedwith 1 or 2 substituents independently selected from R¹¹;

each R¹¹ is independently selected from C₁₋₂ alkyl, C₁₋₂ haloalkyl, F,Cl, D, CN, OR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), and S(O)₂R^(b3);

each R²¹ is independently selected from C₁₋₂ alkyl, F, Cl, D, CN, andOR^(a4); wherein said C₁₋₂ alkyl is optionally substituted with 1substituent selected from R²²;

each R²² is independently selected from F, Cl, CN, and OR^(a6);

R^(c1) and R^(d1) is independently selected from H and C₁₋₂ alkyl;

each R^(a2) is independently selected from H and C₁₋₂ alkyl;

each R^(a3), R^(c3) and R^(d3), is independently selected from H andC₁₋₂ alkyl;

each R^(b3) is independently selected from C₁₋₂ alkyl, and cyclopropyl;

each R^(a4) is independently selected from H and C₁₋₂ alkyl; and

each R^(a6) is independently selected from H and C₁₋₂ alkyl.

In some embodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein:

Cy¹ is selected from phenyl, pyridin-3-yl and pyrazol-4-yl; wherein thephenyl, pyridin-3-yl and pyrazol-4-yl of Cy¹ are each substituted with 1substituent selected from R¹⁰;

R¹ is selected from Cl, C₁₋₂ alkyl, C₁₋₂ haloalkyl, hydroxymethyl, C₁₋₂alkoxy, C₁₋₂ haloalkoxy and C₁₋₂ alkylamino; wherein optionally one ormore H atoms of the C₁₋₂ alkyl, C₁₋₂ haloalkyl, hydroxymethyl, C₁₋₂alkoxy, C₁₋₂ haloalkoxy and C₁₋₂ alkylamino are replaced by one or moreD atoms;

each R² is independently selected from C₁₋₂ alkyl and F; wherein saidC₁₋₂ alkyl is ach optionally substituted with 1 substituent selectedfrom R²¹;

or the R² substituents on the phenyl ring, taken together with the atomsto which they are attached, form a fused 5-membered cycloalkyl ring, ora fused 5-membered heterocycloalkyl ring; wherein each fused 5-memberedheterocycloalkyl ring has at least one ring-forming carbon atom and 1 or2 ring-forming O atoms; and wherein the fused 5-membered cycloalkyl ringand the fused 5-membered heterocycloalkyl ring are each optionallysubstituted with 1 or 2 substituents each independently selected fromR²¹;

n is 0;

R¹⁰ is independently selected from C₁₋₂ alkyl, C₃₋₆ cycloalkyl,azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,pyridinyl, piperazinonyl, diazabicyclo[2.2.1]heptanyl(morpholinyl)ethyl, (pyridinyl)methyl, (triazinyl)methyl, and1-oxa-3,8-diazaspiro[4.5]decan-2-one; wherein the C₁₋₂ alkyl, C₃₋₆cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl,piperazinyl, pyridinyl, piperazinonyl, diazabicyclo[2.2.1]heptanyl(morpholinyl)ethyl, and (pyridinyl)methyl are each optionallysubstituted with 1 or 2 substituents independently selected from R¹¹;

each R¹¹ is independently selected from C₁₋₂ alkyl, CN, OR^(a3),C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), NR^(c3)C(O)R^(b3), andS(O)₂R^(b3);

each R²¹ is independently selected from C₁₋₂ alkyl, F, D, CN, andOR^(a4); wherein said C₁₋₂ alkyl is optionally substituted with 1substituent selected from R²²;

each R²² is OR^(a6);

each R^(a3), R^(c3) and R^(d3), is independently selected from H andC₁₋₂ alkyl;

each R^(b3) is independently selected from C₁₋₂ alkyl, and cyclopropyl;and

each R^(ab) is independently selected from H and C₁₋₂ alkyl.

In some embodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein:

Cy¹ is selected from phenyl, pyridin-3-yl and pyrazol-4-yl; wherein thephenyl, pyridin-3-yl and pyrazol-4-yl of Cy¹ are each optionallysubstituted with 1 substituent selected from R¹⁰;

R¹ is selected from Cl, C₁₋₂ alkyl, C₁₋₂ haloalkyl, cyclopropyl,hydroxymethyl, C₁₋₂ alkoxy, C₁₋₂ haloalkoxy and C₁₋₂ alkylamino; whereinoptionally one or more H atoms of the C₁₋₂ alkyl, C₁₋₂ haloalkyl,cyclopropyl, hydroxymethyl, C₁₋₂ alkoxy, C₁₋₂ haloalkoxy and C₁₋₂alkylamino are replaced by one or more D atoms;

each R² is independently selected from C₃₋₆ cycloalkyl, C₁₋₂ alkyl, C₁₋₂haloalkyl, F, Cl, CN, and OR^(a2); wherein said C₁₋₂ alkyl is optionallysubstituted with 1 substituent selected from R²¹;

or the R² substituents on the phenyl ring, taken together with the atomsto which they are attached, form a fused 5- or 6-membered cycloalkylring, or a fused 5- or 6-membered heterocycloalkyl ring; wherein eachfused 5- or 6-membered heterocycloalkyl ring has at least onering-forming carbon atom and 1 or 2 ring-forming O atoms; and whereinthe fused 5- or 6-membered cycloalkyl ring, or the fused 5- or6-membered heterocycloalkyl ring are each optionally substituted with 1substituent selected from R²¹;

n is 0;

R¹⁰ is independently selected from C₁₋₂ alkyl, C₁₋₂ haloalkyl, C₃₋₆cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl,piperazinyl, pyridinyl, piperazinonyl, diazabicyclo[2.2.1]heptanyl(morpholinyl)ethyl, (pyridinyl)methyl, (triazolyl)methyl,thiomorpholinyl, 1-oxa-3,8-diazaspiro[4.5]decan-2-one,hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, F, Cl, D, CN, OR^(a1), andNR^(c1)R^(d1); wherein the C₁₋₂ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl,azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,pyridinyl, piperazinonyl, diazabicyclo[2.2.1]heptanyl(morpholinyl)ethyl, (pyridinyl)methyl, (triazolyl)methyl,thiomorpholinyl, 1-oxa-3,8-diazaspiro[4.5]decan-2-one, andhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl are each optionally substitutedwith 1 or 2 substituents independently selected from R¹¹;

each R¹¹ is independently selected from C₁₋₂ alkyl, C₁₋₂ haloalkyl, F,Cl, D, CN, C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), NR^(c3)R^(d3),NR^(c3)C(O)R^(b3), and S(O)₂R^(b3), wherein said C₁₋₂ alkyl isoptionally substituted with OR^(a5);

each R²¹ is independently selected from C₁₋₂ alkyl, F, Cl, D, CN, andOR^(a4); wherein said C₁₋₂ alkyl is optionally substituted with 1substituent selected from R²²;

each R²² is independently selected from F, Cl, CN, and OR^(a6);

each R^(a1), R^(c1) and R^(d1) are independently selected from H, C₁₋₂alkyl, and 4-6 membered heterocycloalkyl;

each R^(a2) is independently selected from H and C₁₋₂ alkyl;

each R^(a3), R^(c3) and R^(d3), is independently selected from H andC₁₋₂ alkyl;

each R^(b3) is independently selected from C₁₋₂ alkyl, and cyclopropyl;

each R^(a4) is independently selected from H and C₁₋₂ alkyl;

each R^(a5) is independently selected from H and C₁₋₂ alkyl; and

each R^(a6) is independently selected from H and C₁₋₂ alkyl.

In some embodiments, provided herein is a compound selected from:

-   5-(2,3-dimethylphenyl)-6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine;-   5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine;-   5-(2,3-dimethylphenyl)-6-methoxy-3-(1-((l-methyl-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine;-   5-(2,3-dihydrobenzofuran-7-yl)-6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine;-   2-(3-(6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2-methylphenyl)acetonitrile;-   1-(4-(5-(6-(difluoromethoxy)-5-(2,3-dimethylphenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperazin-1-yl)ethan-1-one;-   4-(6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-1-ol;-   4-(6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile;-   4-(6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-2-ol;-   (4-(6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-1-yl)methanol;-   2-fluoro-4-(6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-1-ol;-   5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-3-(1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine;-   5-(2,3-dihydro-1H-inden-4-yl)-3-(1-(1-ethylpyrrolidin-3-yl)-1H-pyrazol-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine;-   3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)cyclobutanecarbonitrile;-   5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-3-(1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine;-   5-(2,3-dihydro-1H-inden-4-yl)-3-(1-(1-ethylazetidin-3-yl)-1H-pyrazol-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine;-   4-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)-N,N-dimethylpiperidine-1-carboxamide;-   methyl    4-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;-   methyl    3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate;-   1-(3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)ethan-1-one;-   5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-3-(1-(1-(methylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine;-   3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)-N,N-dimethylazetidine-1-carboxamide;-   cyclopropyl(3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)methanone;-   5-(2,3-dihydro-1H-inden-4-yl)-6-ethoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine;-   5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-3-(1-(pyridin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine;-   4-(2-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)ethyl)morpholine;-   3-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine;-   3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)propanenitrile;-   2-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)ethan-1-ol;-   5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-3-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine;-   (trans)-4-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)cyclohexan-1-ol;-   5-(2,3-dimethylphenyl)-N-methyl-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-6-amine;-   6-(difluoromethyl)-5-(2,3-dihydro-1H-inden-4-yl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine;-   (5-(2,3-dihydro-1H-inden-4-yl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-6-yl)methanol;-   5-(2,3-dihydro-1H-inden-4-yl)-N-methyl-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-6-amine;-   (5-(2,3-dimethylphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-6-yl)methanol;-   4-(6-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-2-ol;-   5-(2,3-dimethylphenyl)-6-methyl-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine;-   5-(2,3-dimethylphenyl)-6-methoxy-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine;-   5-(2,3-dimethylphenyl)-3-(6-(4-ethylpiperazin-1-yl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine;-   1-(4-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrzolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperazin-1-yl)ethan-1-one;-   4-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)morpholine;-   4-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-1-methylpiperazin-2-one;-   1-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidin-4-ol;-   (R)-5-(2,3-dimethylphenyl)-3-(6-(3,4-dimethylpiperazin-1-yl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine;-   5-(2,3-dimethylphenyl)-6-(methoxy-d3)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine;-   5-(2,3-dimethylphenyl)-6-methoxy-3-(6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine;-   1-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-N,N-dimethylpiperidine-4-carboxamide;-   1-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-4-methylpiperidine-4-carboxylic    acid;-   3-(4-(5-(2-fluoro-3-methylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)-N,N-dimethylazetidine-1-carboxamide;-   N-((cis)-4-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)cyclohexyl)acetamide;-   5-(2,3-dihydro-1H-inden-4-yl)-3-(6-(2,4-dimethylpiperazin-1-yl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine;-   2-(3-(3-(6-(4-acetylpiperazin-1-yl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2-methylphenyl)acetonitrile;-   2-(3-(6-methoxy-3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2-methylphenyl)acetonitrile;-   5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-3-(6-(pyrrolidin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine;-   4-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)morpholine;-   4-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-N-ethylpiperazine-1-carboxamide;-   4-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperazine-1-carboxamide;-   1-(4-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)phenyl)piperazin-1-yl)ethan-1-one;-   5-(2,3-dihydro-1H-inden-4-yl)-3-(4-(4-isopropylpiperazin-1-yl)phenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine;-   5-(2,3-dihydro-1H-inden-4-yl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine;-   1-(4-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperazin-1-yl)ethan-1-one;-   8-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one;-   5-(2,3-dimethylphenyl)-6-methoxy-3-(1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine;-   3-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine;-   6-methoxy-5-(2-methyl-3-(methyl-d3)phenyl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine;-   1-(4-(4-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethan-1-one;-   methyl    4-(4-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;-   methyl    3-(4-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate;    and-   3-(4-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)-N,N-dimethylazetidine-1-carboxamide;-   or a pharmaceutically acceptable salt of any of the aforementioned.

In some embodiments, provided herein is a compound selected from:

-   2-fluoro-4-(6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-1-ol;-   5-(2,3-dimethylphenyl)-6-methoxy-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine;-   4-(6-methoxy-3-(6-((tetrahydrofuran-3-yl)oxy)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-2-ol;-   4-(6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)    2,3-dihydro-1H-inden-2-d-2-ol;-   4-(6-methoxy-3-(6-(1-methyl-5-oxopyrrolidin-3-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile;-   (S)-1-(4-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidin-1-yl)-2-hydroxypropan-1-one;-   1-(4-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidin-1-yl)-2-hydroxyethan-1-one;-   4-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclohexane-1-carboxylic    acid;-   (3S,4R)-1-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-4-fluoropyrrolidin-3-amine;-   (2S)-1-(4-(5-(5-(2-fluoro-2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidin-1-yl)-2-hydroxypropan-1-one;-   1-(4-(5-(5-(2-fluoro-2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidin-1-yl)-2-hydroxyethan-1-one;-   (7R,8aS)-2-(5-(5-(2-fluoro-2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol;-   5-(2-fluoro-2,3-dihydro-1H-inden-4-yl)-6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine;-   (7S,8aR)-2-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol;-   4-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-1-imino-1λ⁶-thiomorpholine    1-oxide;-   (7R,8aS)-2-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol;-   (S)—N-(1-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)pyrrolidin-3-yl)-2-hydroxy-N-methylacetamide;-   2-(3-(3-(6-(4-(2-hydroxyethyl)piperazin-1-yl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2-methylphenyl)acetonitrile;-   (7R,8aS)-2-(5-(6-methoxy-5-(3-methoxy-2-methylphenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol;-   (7R,8aS)-2-(5-(5-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol;-   (7R,8aS)-2-(5-(5-(2-cyclopropylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol;-   (7R,8aS)-2-(5-(5-(chroman-5-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol;-   (7R,8aS)-2-(5-(5-(2-fluoro-3-methylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol;-   4-(6-methoxy-3-(6-(2-methoxyethoxy)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-2-ol;-   4-(6-methoxy-3-(6-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-2-ol;-   4-(3-(6-cyclopropylpyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-2-ol;    and-   N-(1-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-3-yl)-2-hydroxy-N-methylacetamide;-   or a pharmaceutically acceptable salt of any of the aforementioned.-   In some embodiments, provided herein is a compound selected from:-   1-(4-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidin-1-yl)ethan-1-one;-   1-(4-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidin-1-yl)-2-hydroxyethan-1-one;-   1-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)pyrrolidin-1-yl)-2-hydroxyethan-1-one    (Peak 1);-   1-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)pyrrolidin-1-yl)-2-hydroxyethan-1-one    (Peak 2);-   1-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)pyrrolidin-1-yl)ethan-1-one    (Peak 1);-   1-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)pyrrolidin-1-yl)ethan-1-one    (Peak 2);-   3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-[1,3′-bipyrrolidin]-2′-one    (Peak 1);-   3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-1′-methyl-[1,3′-bipyrrolidin]-2′-one    (Peak 1);-   2-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)pyrrolidin-1-yl)propanamide    (Peak 1);-   5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-3-(6-(1-(methyl-L-prolyl)piperidin-4-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine;-   (3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)pyrrolidin-1-yl)((R)-4-methylmorpholin-3-yl)methanone    (Peak 2);-   4-(6-Methoxy-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile;-   4-(3-(1-(3-Cyanocyclobutyl)-1H-pyrazol-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile;-   4-(3-(1-(1-Acetylpiperidin-4-yl)-1H-pyrazol-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile;-   4-(3-(6-(4-Hydroxycyclohexyl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile;-   4-(3-(6-(4-(2-Hydroxyethyl)piperazin-1-yl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile;-   4-(3-(6-(1-(2-Hydroxyacetyl)piperidin-4-yl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile;-   1-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-2-hydroxyethan-1-one;-   1-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-3-(dimethylamino)propan-1-one;-   (S)-1-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-2-(dimethylamino)propan-1-one;-   (S)-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(1-methylazetidin-2-yl)methanone;-   1-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-2-(4-methylpiperazin-1-yl)ethan-1-one;-   1-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-2-(4-hydroxypiperidin-1-yl)ethan-1-one;-   (R)-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(1-methylazetidin-2-yl)methanone;-   (R)-1-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-2-hydroxypropan-1-one;-   (S)-1-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-2-hydroxypropan-1-one;-   (3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)    ((trans)-3-hydroxycyclobutypmethanone;-   (3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)((cis)-3-hydroxycyclobutyl)methanone;-   (R)-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(4-methylmorpholin-3-yl)methanone;-   (S)-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(4-methylmorpholin-3-yl)methanone;-   (S)-1-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)-2-hydroxyethan-1-one;-   (S)-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(tetrahydrofuran-2-yl)methanone;-   (S)-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(tetrahydrofuran-3-yl)methanone;-   (R)-1-((S)-3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)-2-hydroxypropan-1-one;-   (S)-1-((S)-3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)-2-hydroxypropan-1-one;-   (R)-1-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-3-hydroxybutan-1-one;-   (3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)((1r,3r)-3-hydroxy-3-methylcyclobutyl)methanone;-   (3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)((1s,3s)-3-hydroxy-3-methylcyclobutyl)methanone;-   ((R)-3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)((S)-4-methylmorpholin-3-yl)methanone;-   ((S)-3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)((R)-4-methylmorpholin-3-yl)methanone;-   (3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(1-(hydroxymethyl)cyclobutyl)methanone;-   (S)-(3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(1-ethylazetidin-2-yl)methanone;-   (S)-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(1-(2-fluoroethyl)azetidin-2-yl)methanone;-   (S)-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(1-isopropylazetidin-2-yl)methanone;-   ((S)-3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)((S)-1-(2-fluoroethyl)azetidin-2-yl)methanone;-   ((S)-3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)((trans)-3-hydroxycyclobutyl)methanone;-   ((S)-3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)((cis)-3-hydroxycyclobutypmethanone;-   ((S)-3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)((1s,3r)-3-hydroxy-3-methylcyclobutyl)methanone;-   1-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-2-methoxyethan-1-one;-   1-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-2-(dimethylamino)-2-methylpropan-1-one;-   1-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidine-1-carbonyl)cyclopropane-1-carbonitrile;-   2-((3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)sulfonyl)ethan-1-01;-   2-((3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)sulfonyl)-N,N-dimethylethan-1-amine;-   2-Methoxyethyl    3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate;-   (3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)((1s,3s)-3-methoxycyclobutyl)methanone;-   N-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclopentyl)-N-methylmethanesulfonamide;-   N-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclopentyl)-2-hydroxy-N-methylacetamide    (Peak 1);-   (2S)—N-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclopentyl)-2-hydroxypropanamid;-   N-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclopentyl)-2-hydroxyacetamide;-   2-(1-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)phenyl)-3-azabicyclo[3.1.0]hexan-3-yl)ethan-1-ol;-   4-(3-(4-((1R,5S)-3-(2-Hydroxyethyl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile;-   1-((5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)methyl)piperidin-4-ol;-   5-((5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)methyl)-2-oxa-5-azabicyclo[2.2.1]heptane;-   4-(1-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)ethyl)morpholine;-   7-((5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine;-   4-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-1-(2-hydroxyethyl)piperidine-4-carbonitrile;-   4-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-1-(2-hydroxyacetyl)piperidine-4-carbonitrile;-   2-(3-(6-Methoxy-3-(6-(4-(2-methoxyethyl)piperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2-methylphenyl)acetonitrile;-   4-(6-Methoxy-3-(1-(1-(tetrahydro-2H-pyran-4-carbonyl)piperidin-4-yl-4-d)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile;-   4-(6-Methoxy-3-(1-((S)-1-(2-methoxyacetyl)pyrrolidin-3-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile;-   4-(6-Methoxy-3-(1-((S)-1-((S)-tetrahydrofuran-2-carbonyl)pyrrolidin-3-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile;-   (7R,8aS)-2-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol;-   N-(1-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-3-yl)-2-hydroxy-N-methylacetamide;-   (3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-1-yl)(tetrahydrofuran-2-yl)methanone;-   (S)-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-1-yl)(1-methylpiperidin-2-yl)methanone;-   1-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-1-yl)-2-(dimethylamino)ethan-1-one;-   1-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-1-yl)-3-hydroxypropan-1-one;-   1-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-1-yl)-2-hydroxyethan-1-one;-   (S)-1-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-1-yl)-2-hydroxypropan-1-one;-   N-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclobutyl)-2-hydroxy-N-methylacetamide;-   1-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-1-yl-3-d)-2-hydroxyethan-1-one;-   Methyl    4-(5-(5-(1-Cyano-2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidine-1-carboxylate;-   4-(6-Methoxy-3-(6-(1-(morpholine-4-carbonyl)piperidin-4-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile,    Peak 2;-   4-(3-(6-(1-Acetylpiperidin-4-yl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile,    Peak 2;-   4-(3-(6-(1-Acetylpyrrolidin-3-yl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile;-   4-(6-Methoxy-3-(6-(1-(morpholine-4-carbonyl)pyrrolidin-3-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile;-   4-(3-(1-(Cyanomethyl)-1H-pyrazol-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile;-   4-(6-Methoxy-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile;-   3-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-1-yl)propanenitrile;-   N-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclobutyl)-2-methoxy-N-methylacetamide;-   N-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclobutyl)-3-hydroxy-N-methylpropanamide;-   (S)—N-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclobutyl)-2-hydroxy-N-methylpropanamide;-   1-(1-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-hydroxyethan-1-one;-   (R)1-(1-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-hydroxyethan-1-one,    two enantiomers;-   (S)1-(1-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-hydroxyethan-1-one,    two enantiomers;-   (1-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)((R)-4-methylmorpholin-3-yl)methanone;-   5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-3-(6-(3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine-   2-(1-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)ethan-1-ol;-   (R)    2-(1-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)ethan-1-ol,    two enantiomers;-   (S)    2-(1-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)ethan-1-ol,    two enantiomers;-   3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-1-((R)-4-methylmorpholine-3-carbonyl)pyrrolidine-3-carbonitrile;-   (R)-4-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-1-(4-methylmorpholine-3-carbonyl)piperidine-4-carbonitrile;-   1-(1-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-hydroxyethan-1-one;-   3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-1-(2-hydroxyacetyl)pyrrolidine-3-carbonitrile;-   (S)-4-((5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)methyl)-1,3-dimethylpiperazin-2-one;    and-   (1R,4R)-5-((5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)methyl)-2-oxa-5-azabicyclo[2.2.1]heptane;

or a pharmaceutically acceptable salt of any of the aforementioned.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment. Conversely,various features of the invention which are, for brevity, described inthe context of a single embodiment, can also be provided separately orin any suitable sub combination.

At various places in the present specification, substituents ofcompounds of the invention are disclosed in groups or in ranges. It isspecifically intended that the invention include each and everyindividual subcombination of the members of such groups and ranges. Forexample, the term “C₁₋₆ alkyl” is specifically intended to individuallydisclose methyl, ethyl, C₃ alkyl, C₄ alkyl, C₅ alkyl, and C₆ alkyl.

At various places in the present specification various aryl, heteroaryl,cycloalkyl, and heterocycloalkyl rings are described. Unless otherwisespecified, these rings can be attached to the rest of the molecule atany ring member as permitted by valency. For example, the term “apyridine ring” or “pyridinyl” may refer to a pyridin-2-yl, pyridin-3-yl,or pyridin-4-yl ring.

The term “n-membered” where n is an integer typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is n. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a10-membered cycloalkyl group.

For compounds of the invention in which a variable appears more thanonce, each variable can be a different moiety independently selectedfrom the group defining the variable. For example, where a structure isdescribed having two R groups that are simultaneously present on thesame compound, the two R groups can represent different moietiesindependently selected from the group defined for R.

As used herein, the phrase “optionally substituted” means unsubstitutedor substituted.

The term “substituted” means that an atom or group of atoms formallyreplaces hydrogen as a “substituent” attached to another group. The term“substituted”, unless otherwise indicated, refers to any level ofsubstitution, e.g., mono-, di-, tri-, tetra- or penta-substitution,where such substitution is permitted. The substituents are independentlyselected, and substitution may be at any chemically accessible position.It is to be understood that substitution at a given atom is limited byvalency. It is to be understood that substitution at a given atomresults in a chemically stable molecule. A single divalent substituent,e.g., oxo, can replace two hydrogen atoms.

As used herein, the term “C_(i-j),” where i and j are integers, employedin combination with a chemical group, designates a range of the numberof carbon atoms in the chemical group with i-j defining the range. Forexample, C₁₋₆ alkyl refers to an alkyl group having 1, 2, 3, 4, 5, or 6carbon atoms.

As used herein, the term “alkyl,” employed alone or in combination withother terms, refers to a saturated hydrocarbon group that may bestraight-chain or branched. An alkyl group formally corresponds to analkane with one C—H bond replaced by the point of attachment of thealkyl group to the remainder of the compound. In some embodiments, thealkyl group contains 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples ofalkyl moieties include, but are not limited to, chemical groups such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, n-pentyl, 2-methyl-1-butyl, 3-pentyl, n-hexyl,1,2,2-trimethylpropyl, and the like. In some embodiments, the alkylgroup is methyl, ethyl, or propyl.

As used herein, the term “C_(i-j) alkylene,” employed alone or incombination with other terms, means a saturated divalent linkinghydrocarbon group that may be straight-chain or branched, having i to jcarbons. In some embodiments, the alkylene group contains from 1 to 4carbon atoms, from 1 to 3 carbon atoms, or from 1 to 2 carbon atoms.Examples of alkylene moieties include, but are not limited to, chemicalgroups such as methylene, ethylene, 1,1-ethylene, 1,2-ethylene,1,3-propylene, 1,2-propylene, 1,1-propylene, isopropylene, and the like.

As used herein, “alkenyl,” employed alone or in combination with otherterms, refers to a straight-chain or branched hydrocarbon groupcorresponding to an alkyl group having one or more carbon-carbon doublebonds. An alkenyl group formally corresponds to an alkene with one C—Hbond replaced by the point of attachment of the alkenyl group to theremainder of the compound. In some embodiments, the alkenyl moietycontains 2 to 6 or 2 to 4 carbon atoms. Example alkenyl groups include,but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl,sec-butenyl, and the like.

As used herein, “alkynyl,” employed alone or in combination with otherterms, refers to a straight-chain or branched hydrocarbon groupcorresponding to an alkyl group having one or more carbon-carbon triplebonds. An alkynyl group formally corresponds to an alkyne with one C—Hbond replaced by the point of attachment of the alkyl group to theremainder of the compound. In some embodiments, the alkynyl moietycontains 2 to 6 or 2 to 4 carbon atoms. Example alkynyl groups include,but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, and the like.

As used herein, “halo” or “halogen”, employed alone or in combinationwith other terms, includes fluoro, chloro, bromo, and iodo. In someembodiments, halo is F or Cl. In some embodiments, halo is F.

As used herein, the term “haloalkyl,” employed alone or in combinationwith other terms, refers to an alkyl group in which one or more of thehydrogen atoms has been replaced by a halogen atom, having up to thefull valency of halogen atom substituents, which may either be the sameor different. In some embodiments, the halogen atoms are fluoro atoms.In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3carbon atoms. Example haloalkyl groups include CF₃, C₂F₅, CHF₂, CCl₃,CHCl₂, C₂Cl₅, and the like.

As used herein, the term “alkoxy,” employed alone or in combination withother terms, refers to a group of formula —O-alkyl. In some embodiments,the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examplealkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy andisopropoxy), t-butoxy, and the like. In some embodiments, alkoxy ismethoxy.

As used herein, “haloalkoxy,” employed alone or in combination withother terms, refers to a group of formula —O-(haloalkyl). In someembodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.An example haloalkoxy group is —OCF₃.

As used herein, “amino,” employed alone or in combination with otherterms, refers to NH₂.

As used herein, the term “alkylamino,” employed alone or in combinationwith other terms, refers to a group of formula —NH(alkyl). In someembodiments, the alkylamino group has 1 to 6 or 1 to 4 carbon atoms.Example alkylamino groups include methylamino, ethylamino, propylamino(e.g., n-propylamino and isopropylamino), and the like.

As used herein, the term “dialkylamino,” employed alone or incombination with other terms, refers to a group of formula —N(alkyl)₂.Example dialkylamino groups include dimethylamino, diethylamino,dipropylamino (e.g., di(n-propyl)amino and di(isopropyl)amino), and thelike. In some embodiments, each alkyl group independently has 1 to 6 or1 to 4 carbon atoms.

As used herein, the term “alkylthio,” employed alone or in combinationwith other terms, refers to a group of formula —S-alkyl. In someembodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term “cycloalkyl,” employed alone or in combinationwith other terms, refers to a non-aromatic cyclic hydrocarbon includingcyclized alkyl and alkenyl groups. The term “C_(n-m) cycloalkyl” refersto a cycloalkyl that has n to m ring member carbon atoms. Cycloalkylgroups can include mono- or polycyclic (e.g., having 2, 3, or 4 fused,bridged, or spiro rings) ring systems. Also included in the definitionof cycloalkyl are moieties that have one or more aromatic rings (e.g.,aryl or heteroaryl rings) fused (i.e., having a bond in common with) tothe cycloalkyl ring, for example, benzo derivatives of cyclopentane,cyclohexene, cyclohexane, and the like, or pyrido derivatives ofcyclopentane or cyclohexane. A cycloalkyl group containing a fusedaromatic ring can be attached through any ring-forming atom including aring-forming atom of the fused aromatic ring. Ring-forming carbon atomsof a cycloalkyl group can be optionally substituted by oxo. Cycloalkylgroups also include cycloalkylidenes. The term “cycloalkyl” alsoincludes bridgehead cycloalkyl groups (e.g., non-aromatic cyclichydrocarbon moieties containing at least one bridgehead carbon, such asadmantan-1-yl) and spirocycloalkyl groups (e.g., non-aromatichydrocarbon moieties containing at least two rings fused at a singlecarbon atom, such as spiro[2.5]octane and the like). In someembodiments, the cycloalkyl group has 3 to 10 ring members, or 3 to 7ring members, or 3 to 6 ring members. In some embodiments, thecycloalkyl group is monocyclic or bicyclic. In some embodiments, thecycloalkyl group is monocyclic. In some embodiments, the cycloalkylgroup is a C₃₋₇ monocyclic cycloalkyl group. Example cycloalkyl groupsinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl,norbornyl, norpinyl, norcarnyl, tetrahydronaphthalenyl,octahydronaphthalenyl, indanyl, and the like. In some embodiments, thecycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

As used herein, the term “heterocycloalkyl,” employed alone or incombination with other terms, refers to a non-aromatic ring or ringsystem, which may optionally contain one or more alkenylene oralkynylene groups as part of the ring structure, which has at least oneheteroatom ring member independently selected from nitrogen, sulfur,oxygen, and phosphorus, and which has 4-14 ring members, 4-10 ringmembers, 4-7 ring members, or 4-6 ring members. Included within the term“heterocycloalkyl” are monocyclic 4-, 5-, 6- and 7-memberedheterocycloalkyl groups. Heterocycloalkyl groups can include mono- orpolycyclic (e.g., having 2, 3 or 4 fused, bridged, or spiro rings) orspirocyclic ring systems. In some embodiments, the heterocycloalkylgroup is a monocyclic or bicyclic group having 1, 2, 3, or 4 heteroatomsindependently selected from nitrogen, sulfur and oxygen. Also includedin the definition of heterocycloalkyl are moieties that have one or morearomatic rings (e.g., aryl or heteroaryl rings) fused (i.e., having abond in common with) to the non-aromatic heterocycloalkyl ring, forexample, 1,2,3,4-tetrahydro-quinoline and the like. Heterocycloalkylgroups can also include bridgehead heterocycloalkyl groups (e.g., aheterocycloalkyl moiety containing at least one bridgehead atom, such asazaadmantan-1-yl and the like) and spiroheterocycloalkyl groups (e.g., aheterocycloalkyl moiety containing at least two rings fused at a singleatom, such as [1,4-dioxa-8-aza-spiro[4.5]decan-N-yl] and the like). Insome embodiments, the heterocycloalkyl group has 3 to 10 ring-formingatoms, 4 to 10 ring-forming atoms, or 3 to 8 ring forming atoms. In someembodiments, the heterocycloalkyl group has 1 to 5 heteroatoms, 1 to 4heteroatoms, 1 to 3 heteroatoms, or 1 to 2 heteroatoms. The carbon atomsor heteroatoms in the ring(s) of the heterocycloalkyl group can beoxidized to form a carbonyl, an N-oxide, or a sulfonyl group (or otheroxidized linkage) or a nitrogen atom can be quaternized. In someembodiments, an S atom in the ring of the heterocycloalkyl group can beoxidized to form an imino-λ⁶-sulfanone group (i.e., the S atom issubstituted with an ═O group and an ═NH group). In some embodiments, theheterocycloalkyl portion is a C₂₋₇ monocyclic heterocycloalkyl group. Insome embodiments, the heterocycloalkyl group is a morpholine ring,pyrrolidine ring, piperazine ring, piperidine ring, dihydropyran ring,tetrahydropyran ring, tetrahyropyridine, azetidine ring, ortetrahydrofuran ring. In some embodiments, the heterocycloalkyl is a 4-7membered heterocycloalkyl moiety having carbon and 1, 2, or 3heteroatoms independently selected from N, O and S. In some embodiments,the heterocycloalkyl is 4-10 membered heterocycloalkyl moiety havingcarbon and 1, 2, or 3 heteroatoms independently selected from N, O andS.

As used herein, the term “aryl,” employed alone or in combination withother terms, refers to a monocyclic or polycyclic (e.g., having 2 fusedrings) aromatic hydrocarbon moiety, such as, but not limited to, phenyl,1-naphthyl, 2-naphthyl, and the like. In some embodiments, aryl groupshave from 6 to 10 carbon atoms or 6 carbon atoms. In some embodiments,the aryl group is a monocyclic or bicyclic group. In some embodiments,the aryl group is phenyl.

As used herein, the term “genetic alterations” employed alone or incombination with other terms, refers to mutations, fusions,rearrangements (translocations, deletions, inversions) andamplifications of genes.

As used herein, the term “heteroaryl” or “heteroaromatic” employed aloneor in combination with other terms, refers to a monocyclic or polycyclic(e.g., having 2 or 3 fused rings) aromatic hydrocarbon moiety, havingone or more heteroatom ring members independently selected fromnitrogen, sulfur and oxygen. In some embodiments, the heteroaryl groupis a monocyclic or bicyclic group having 1, 2, 3, or 4 heteroatomsindependently selected from nitrogen, sulfur and oxygen. Exampleheteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl,pyrazinyl, pyridazinyl, triazinyl, furyl, thienyl, imidazolyl,thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl,benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl,1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl,indolinyl, pyrrolyl, azolyl, quinolinyl, isoquinolinyl, benzisoxazolyl,imidazo[1,2-b]thiazolyl, pyridone, or the like. The carbon atoms orheteroatoms in the ring(s) of the heteroaryl group can be oxidized toform a carbonyl, an N-oxide, or a sulfonyl group (or other oxidizedlinkage) or a nitrogen atom can be quaternized, provided the aromaticnature of the ring is preserved. In one embodiment the heteroaryl groupis a 5 to 10 membered heteroaryl group. In another embodiment theheteroaryl group is a 5 to 6 membered heteroaryl group. In someembodiments, the heteroaryl is a 5-6 membered heteroaryl moiety havingcarbon and 1, 2, or 3 heteroatoms independently selected from N, O andS. In some embodiments, the heteroaryl is a 5-10 membered heteroarylmoiety having carbon and 1, 2, or 3 heteroatoms independently selectedfrom N, O and S. In some embodiments, the heteroaryl has 5-6 ring atomsand 1 or 2 heteroatom ring members independently selected from nitrogen,sulfur and oxygen. In some embodiments, no more than 2 heteroatoms of a5-membered heteroaryl moiety are N.

A five-membered heteroaryl ring is a heteroaryl group having five ringatoms wherein one or more (e.g., 1, 2 or 3) ring atoms are independentlyselected from N, O and S. Exemplary five-membered ring heteroarylsinclude thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl,pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl,1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl,1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl,1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.

A six-membered heteroaryl ring is a heteroaryl group having six ringatoms wherein one or more (e.g., 1, 2 or 3) ring atoms are independentlyselected from N, O and S. Exemplary six-membered ring heteroaryls arepyridyl, pyrazinyl, pyrimidinyl, triazinyl, isoindolyl, and pyridazinyl.

The term “oxo” refers to an oxygen atom as a divalent substituent,forming a carbonyl group when attached to carbon, or attached to aheteroatom forming a sulfoxide or sulfone group, or an N-oxide group. Insome embodiments, heterocyclic groups may be optionally substituted by 1or 2 oxo (═O) substituents.

The term “oxidized” in reference to a ring-forming N atom refers to aring-forming N-oxide.

The term “oxidized” in reference to a ring-forming S atom refers to aring-forming sulfonyl or ring-forming sulfinyl.

The term “aromatic” refers to a carbocycle or heterocycle having one ormore polyunsaturated rings having aromatic character (i.e., having(4n+2) delocalized π (pi) electrons where n is an integer).

At certain places, the definitions or embodiments refer to specificrings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwiseindicated, these rings can be attached to any ring member provided thatthe valency of the atom is not exceeded. For example, an azetidine ringmay be attached at any position of the ring, whereas an azetidin-3-ylring is attached at the 3-position.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent invention that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Many geometric isomers ofolefins, C═N double bonds, and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present invention. Cis and trans geometric isomers of thecompounds of the present invention are described and may be isolated asa mixture of isomers or as separated isomeric forms.

Resolution of racemic mixtures of compounds can be carried out bymethods known in the art. An example method includes fractionalrecrystallization using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, for example, optically activeacids, such as the D and L forms of tartaric acid, diacetyltartaricacid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid orthe various optically active camphorsulfonic acids. Other resolvingagents suitable for fractional crystallization methods includestereoisomerically pure forms of methylbenzylamine (e.g., S and R forms,or diastereomerically pure forms), 2-phenylglycinol, norephedrine,ephedrine, N-methylephedrine, cyclohexylethylamine,1,2-diaminocyclohexane, and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

In some embodiments, the compounds of the invention have the(R)-configuration. In other embodiments, the compounds have the(5)-configuration. In compounds with more than one chiral centers, eachof the chiral centers in the compound may be independently (R) or (5),unless otherwise indicated.

Compounds of the invention also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone-enol pairs, amide-imidic acidpairs, lactam-lactim pairs, enamine-imine pairs, and annular forms wherea proton can occupy two or more positions of a heterocyclic system, forexample, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be inequilibrium or sterically locked into one form by appropriatesubstitution.

Compounds of the invention also include all isotopes of atoms occurringin the intermediates or final compounds. Isotopes include those atomshaving the same atomic number but different mass numbers. For example,isotopes of hydrogen include tritium and deuterium. One or moreconstituent atoms of the compounds of the invention can be replaced orsubstituted with isotopes of the atoms in natural or non-naturalabundance. In some embodiments, the compound includes at least onedeuterium atom. For example, one or more hydrogen atoms in a compound ofthe present disclosure can be replaced or substituted by deuterium. Insome embodiments, the compound includes two or more deuterium atoms. Insome embodiments, the compound includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11 or 12 deuterium atoms. Synthetic methods for including isotopes intoorganic compounds are known in the art (Deuterium Labeling in OrganicChemistry by Alan F. Thomas (New York, N.Y., Appleton-Century-Crofts,1971; The Renaissance of H/D Exchange by Jens Atzrodt, Volker Derdau,Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007,7744-7765; The Organic Chemistry of Isotopic Labelling by James R.Hanson, Royal Society of Chemistry, 2011). Isotopically labeledcompounds can used in various studies such as NMR spectroscopy,metabolism experiments, and/or assays.

Substitution with heavier isotopes such as deuterium, may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample, increased in vivo half-life or reduced dosage requirements, andhence may be preferred in some circumstances. (A. Kerekes et.al. J. Med.Chem. 2011, 54, 201-210; R. Xu et.al. J. Label Compd. Radiopharm. 2015,58, 308-312).

The term, “compound,” as used herein is meant to include allstereoisomers, geometric isomers, tautomers, and isotopes of thestructures depicted. The term is also meant to refer to compounds of theinventions, regardless of how they are prepared, e.g., synthetically,through biological process (e.g., metabolism or enzyme conversion), or acombination thereof.

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.,in the form of hydrates and solvates) or can be isolated. When in thesolid state, the compounds described herein and salts thereof may occurin various forms and may, e.g., take the form of solvates, includinghydrates. The compounds may be in any solid state form, such as apolymorph or solvate, so unless clearly indicated otherwise, referencein the specification to compounds and salts thereof should be understoodas encompassing any solid state form of the compound.

In some embodiments, the compounds of the invention, or salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, for example, a composition enriched in the compounds of theinvention. Substantial separation can include compositions containing atleast about 50%, at least about 60%, at least about 70%, at least about80%, at least about 90%, at least about 95%, at least about 97%, or atleast about 99% by weight of the compounds of the invention, or saltthereof. Methods for isolating compounds and their salts are routine inthe art.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The present invention also includes pharmaceutically acceptable salts ofthe compounds described herein. As used herein, “pharmaceuticallyacceptable salts” refers to derivatives of the disclosed compoundswherein the parent compound is modified by converting an existing acidor base moiety to its salt form. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts of the present invention include the non-toxic salts ofthe parent compound formed, for example, from non-toxic inorganic ororganic acids. The pharmaceutically acceptable salts of the presentinvention can be synthesized from the parent compound which contains abasic or acidic moiety by conventional chemical methods. Generally, suchsalts can be prepared by reacting the free acid or base forms of thesecompounds with a stoichiometric amount of the appropriate base or acidin water or in an organic solvent, or in a mixture of the two;generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g.,methanol, ethanol, iso-propanol, or butanol) or acetonitrile (ACN) arepreferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), eachof which is incorporated herein by reference in its entirety.

The following abbreviations may be used herein: AcOH (acetic acid); Ac₂O(acetic anhydride); aq. (aqueous); atm. (atmosphere(s)); Boc(t-butoxycarbonyl); br (broad); Cbz (carboxybenzyl); calc. (calculated);d (doublet); dd (doublet of doublets); DCM (dichloromethane); DEAD(diethyl azodicarboxylate); DIAD (N,N′-diisopropyl azidodicarboxylate);DIPEA (N,N-diisopropylethylamine); DMF (N,N-dimethylformamide); Et(ethyl); EtOAc (ethyl acetate); g (gram(s)); h (hour(s)); HATU(N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate); HCl (hydrochloric acid); HPLC (high performanceliquid chromatography); Hz (hertz); J (coupling constant); LCMS (liquidchromatography mass spectrometry); m (multiplet); M (molar); mCPBA(3-chloroperoxybenzoic acid); MgSO₄ (magnesium sulfate); MS (Massspectrometry); Me (methyl); MeCN (acetonitrile); MeOH (methanol); mg(milligram(s)); min. (minutes(s)); mL (milliliter(s)); mmol(millimole(s)); N (normal); NaHCO₃ (sodium bicarbonate); NaOH (sodiumhydroxide); Na₂SO₄ (sodium sulfate); NH₄Cl (ammonium chloride); NH₄OH(ammonium hydroxide); NIS (N-iodosuccinimide); nM (nanomolar); NMR(nuclear magnetic resonance spectroscopy); OTf(trifluoromethanesulfonate); Pd (palladium); Ph (phenyl); pM(picomolar); PMB (para-methoxybenzyl), POCl₃ (phosphoryl chloride);RP-HPLC (reverse phase high performance liquid chromatography); s(singlet); SEM (2-trimethylsilylethoxymethyl); t (triplet or tertiary);TBS (tert-butyldimethylsilyl); tert (tertiary); tt (triplet oftriplets); t-Bu (tert-butyl); TFA (trifluoroacetic acid); THF(tetrahydrofuran); μg (microgram(s)); μL (microliter(s)); μM(micromolar); wt % (weight percent).

Synthesis

Compounds of the invention, including salts thereof, can be preparedusing known organic synthesis techniques and according to variouspossible synthetic routes.

The reactions for preparing compounds of the invention can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynonreactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

Preparation of compounds of the invention can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups can be found, for example, in T. W. Greene and P. G.M. Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons,Inc., New York (1999), which is incorporated herein by reference in itsentirety.

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), ormass spectrometry, or by chromatography such as high performance liquidchromatography (HPLC) or thin layer chromatography.

The expressions, “ambient temperature,” “room temperature,” and “r.t.”,as used herein, are understood in the art, and refer generally to atemperature, e.g. a reaction temperature, that is about the temperatureof the room in which the reaction is carried out, for example, atemperature from about 20° C. to about 30° C.

Compounds of formula (I) with a variety of substitution at position Cy¹can be prepared, using a process as illustrated in Scheme 1. In theprocess depicted in Scheme 1, the halo substituent in compounds offormula 1-1 can undergo a cross-coupling reaction, including Suzuki(Tetrahedron 2002, 58, 9633-9695) (e.g., in the presence of a palladiumcatalyst, such as Xphos Pd G2, and a base, such as potassium phosphate),Negishi (ACS Catalysis 2016, 6, 1540-1552) or Stille (ACS Catalysis2015, 5, 3040-3053) (e.g., in the presence of a palladium(0) catalyst,such as tetrakis(triphenylphosphine)palladium(0)), and others, to givecompounds of formula 1-2. A protective group in the compounds of formula1-2 can be removed in acidic conditions (e.g., in the presence of TFA orHCl) to give compounds of formula 1-3. These compounds can be furtherhalogenated with one of the halogenation agents (e.g., NIS or iodine),followed by NH protection with a suitable protecting group (e.g., Boc),to afford compounds of formula 1-4. A cross-coupling reaction of 1-4,including Suzuki (e.g., in the presence of a palladium catalyst, such asXphos Pd G2, and a base, such as potassium phosphate), Negishi or Stille(e.g., in the presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0)), followed by deprotection ofthe protective group, affords compounds of formula (I).

Alternatively, the compounds of formula (I) can be prepared, using aprocess as illustrated in Scheme 2. A protective group in the compoundsof formula 1-1 can be removed in acidic conditions (e.g., in thepresence of TFA or HCl) to give compounds of formula 2-1. Thesecompounds can be iodinated with one of the iodination agents (e.g., NISor iodine), followed by NH protection with a suitable protecting group(e.g., Boc), to afford compounds of formula 2-2. A cross-couplingreaction of 2-2, including Suzuki (e.g., in the presence of a palladiumcatalyst, such as Pd(dppf)Cl₂, and a base, such as potassium phosphate),results in the formation of the compounds of formula 2-3. The secondcross-coupling reaction of 2-3, including Suzuki (e.g., in the presenceof a palladium catalyst, such as Xphos Pd G2, and a base, such aspotassium phosphate), Negishi or Stille (e.g., in the presence of apalladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0)), followed by deprotection ofthe protective group, affords compounds of formula (I).

Methods of Use

Compounds of the present disclosure can inhibit the activity of the FGFRenzyme. For example, compounds of the present disclosure can be used toinhibit activity of an FGFR enzyme in a cell or in an individual orpatient in need of inhibition of the enzyme by administering aninhibiting amount of one or more compounds of the present disclosure tothe cell, individual, or patient. Compounds of the present disclosurecan be used to inhibit activity of the FGFR3 enzyme in a cell or in anindividual or patient in need of inhibition of the enzyme byadministering an inhibiting amount of one or more compounds of thepresent disclosure to the cell, individual, or patient. Compounds of thepresent disclosure can be used to inhibit activity of the FGFR2 enzymein a cell or in an individual or patient in need of inhibition of theenzyme by administering an inhibiting amount of one or more compounds ofthe present disclosure to the cell, individual, or patient. Compounds ofthe present disclosure can be used to inhibit the activity of an FGFR3and an FGFR2 enzyme in a cell or in an individual or patient in need ofinhibition of the enzyme by administering an inhibiting amount of acompound of the disclosure to the cell, individual, or patient.

In some embodiments, the compounds of the disclosure have selectiveinhibitory activity for the enzyme FGFR3 over FGFR1. In someembodiments, the selectivity of the compounds of the disclosure forFGFR3 over FGFR1 is 10-fold to 25-fold, or 25-fold to 50-fold. In someembodiments, the compounds of the disclosure have selective inhibitoryactivity for the enzyme FGFR3 over FGFR4. In some embodiments, theselectivity of the compounds of the disclosure for FGFR3 over FGFR4 is10-fold to 25-fold, 25-fold to 50-fold, or 50-fold to 100-fold. In someembodiments, the compounds of the disclosure have selective inhibitoryactivity for the enzyme FGFR3 over FGFR2. In some embodiments, theselectivity of the compounds of the disclosure for FGFR3 over FGFR2 is1.5-fold to 2-fold, or 2-fold to 3-fold.

In some embodiments, the inhibitory activity of the compounds ofExamples 1 through 98 for FGFR3 over the inhibitory activity of thecompounds of US2018/0072718 for FGFR3 is 10-fold or more, e.g., 50-fold,100-fold, 250-fold, 500-fold, 750-fold, 1000-fold, etc.

In some embodiments, the compounds of the present disclosure haveselective inhibitory activity for the enzyme FGFR3 over FGFR1. Withoutbeing bound to a particular theory, it is believed that FGFR1 isassociated with certain side effects such as FGFR1-drivenhypophosphatemia. Compounds of the present disclosure can beadvantageous over nonselective FGFR inhibitors (e.g., compounds thathave similar inhibitory activity against, for example, both FGFR1 andFGFR3) because the compounds of the present disclosure have thepotential for little or no FGFR1-driven hypophosphatemia side effects,and potentially allow for higher maximum dosage while avoiding sideeffects associated with FGFR1.

In some embodiments, the compounds of the disclosure have selectiveinhibitory activity for the enzyme FGFR2 over FGFR1. In someembodiments, the selectivity of the compounds of the disclosure forFGFR2 over FGFR1 is 10-fold to 25-fold, or 25-fold to 50-fold. In someembodiments, the compounds of the disclosure have selective inhibitoryactivity for the enzyme FGFR2 over FGFR4. In some embodiments, theselectivity of the compounds of the disclosure for FGFR2 over FGFR4 is10-fold to 25-fold, 25-fold to 50-fold, or 50-fold to 100-fold.

As FGFR inhibitors, the compounds of the present disclosure are usefulin the treatment of various diseases associated with abnormal expressionor activity of the FGFR enzyme or FGFR ligands. Compounds which inhibitFGFR will be useful in providing a means of preventing the growth orinducing apoptosis in tumors, particularly by inhibiting angiogenesis.It is therefore anticipated that compounds of the present disclosurewill prove useful in treating or preventing proliferative disorders suchas cancers. In particular, tumors with activating mutants of receptortyrosine kinases or upregulation of receptor tyrosine kinases may beparticularly sensitive to the inhibitors.

In certain embodiments, the disclosure provides a method for treating aFGFR-mediated disorder in a patient in need thereof, comprising the stepof administering to said patient a compound according to the invention,or a pharmaceutically acceptable composition thereof.

In some embodiments, diseases and indications that are treatable usingthe compounds of the present disclosure include, but are not limited tohematological cancers, sarcomas, lung cancers, gastrointestinal cancers,genitourinary tract cancers, liver cancers, bone cancers, nervous systemcancers, gynecological cancers, and skin cancers.

In some embodiments, cancers that are treatable using the compounds ofthe present disclosure are selected from adenocarcinoma, bladder cancer,breast cancer, cervical cancer, cholangiocarcinoma, colorectal cancer,endometrial cancer, esophageal cancer, gall bladder cancer, gastriccancer, glioma, head and neck cancer, hepatocellular cancer, kidneycancer, liver cancer, lung cancer, melanoma, ovarian cancer, pancreaticcancer, prostate cancer, rhabdomyosarcoma, skin cancer, thyroid cancer,leukemia, multiple myeloma, chronic lymphocytic lymphoma, adult T cellleukemia, B-cell lymphoma, acute myelogenous leukemia, Hodgkin's ornon-Hodgkin's lymphoma, Waldenstrom's Macroglubulinemia, hairy celllymphoma, and Burkett's lymphoma.

In some embodiments, cancers that are treatable using the compounds ofthe present disclosure are selected from hepatocellular cancer, bladdercancer, breast cancer, cervical cancer, colorectal cancer, endometrialcancer, gastric cancer, head and neck cancer, kidney cancer, livercancer, lung cancer, ovarian cancer, prostate cancer, esophageal cancer,gall bladder cancer, pancreatic cancer, thyroid cancer, skin cancer,leukemia, multiple myeloma, chronic lymphocytic lymphoma, adult T cellleukemia, B-cell lymphoma, acute myelogenous leukemia, Hodgkin's ornon-Hodgkin's lymphoma, Waldenstrom's Macroglubulinemia, hairy celllymphoma, Burkett's lymphoma, glioblastoma, melanoma, and rhabdosarcoma.

In some embodiments, said cancer is selected from adenocarcinoma,bladder cancer, breast cancer, cervical cancer, cholangiocarcinoma,endometrial cancer, gastric cancer, glioma, head and neck cancer, lungcancer, ovarian cancer, leukemia, and multiple myeloma.

In some embodiments, cancers that are treatable using the compounds ofthe present disclosure are selected from hepatocellular cancer, breastcancer, bladder cancer, colorectal cancer, melanoma, mesothelioma, lungcancer, prostate cancer, pancreatic cancer, testicular cancer, thyroidcancer, squamous cell carcinoma, glioblastoma, neuroblastoma, uterinecancer, and rhabdosarcoma.

A cancer characterized by an FGFR2 and/or FGFR3 alteration includesbladder cancers (FGFR3 mutation or fusion), cholangiocarcinoma (FGFR2fusion) and gastric cancer (FGFR2 amplification).

Compounds of the invention can be used to treat cancer patients withFGFR2/3 alterations, including mutations, fusion, rearrangement, andamplification. FGFR2/3 alterations were found in a subset ofcholangiocarcinoma, urothelial carcinoma, multiple myeloma, gastricadenocarcinoma, glioma, endometrial carcinoma, ovarian carcinoma,cervical cancer, lung cancer and breast cancer. Moreover, the compoundsof the invention can be used to target patients progressing on pan-FGFRinhibitor treatment due to acquirement of gatekeeper mutations(V555M/L/F/I in FGFR3, V564M/L/F/I in FGFR2). Also Compounds of theinvention can be used to treat cancer where FGFR2/3 signaling isinvolved in the resistance to other targeted therapies, for example, ithas the potential to overcome resistance to CDK4/6 inhibitors in ERpositive breast cancers.

Exemplary hematological cancers include lymphomas and leukemias such asacute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML),acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL),chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma(DLBCL), mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsedor refractory NHL and recurrent follicular), Hodgkin lymphoma,myeloproliferative diseases (e.g., primary myelofibrosis (PMF),polycythemia vera (PV), essential thrombocytosis (ET), 8p11myeloproliferative syndrome), myelodysplasia syndrome (MDS), T-cellacute lymphoblastic lymphoma (T-ALL), multiple myeloma, cutaneous T-celllymphoma, adult T-cell leukemia, Waldenstrom's Macroglubulinemia, hairycell lymphoma, marginal zone lymphoma, chronic myelogenic lymphoma andBurkitt's lymphoma.

Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma,osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma,myxoma, rhabdomyoma, rhabdosarcoma, fibroma, lipoma, harmatoma,lymphosarcoma, leiomyosarcoma, and teratoma.

Exemplary lung cancers include non-small cell lung cancer (NSCLC), smallcell lung cancer, bronchogenic carcinoma (squamous cell,undifferentiated small cell, undifferentiated large cell,adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma,chondromatous hamartoma, mesothelioma, pavicellular and non-pavicellularcarcinoma, bronchial adenoma and pleuropulmonary blastoma.

Exemplary gastrointestinal cancers include cancers of the esophagus(squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma),stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (exocrinepancreatic carcinoma, ductal adenocarcinoma, insulinoma, glucagonoma,gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma,lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma,lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubularadenoma, villous adenoma, hamartoma, leiomyoma), colorectal cancer, gallbladder cancer and anal cancer.

Exemplary genitourinary tract cancers include cancers of the kidney(adenocarcinoma, Wilm's tumor [nephroblastoma], renal cell carcinoma),bladder and urethra (squamous cell carcinoma, transitional cellcarcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis(seminoma, teratoma, embryonal carcinoma, teratocarcinoma,choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma,fibroadenoma, adenomatoid tumors, lipoma) and urothelial carcinoma.

Exemplary liver cancers include hepatoma (hepatocellular carcinoma),cholangiocarcinoma, hepatoblastoma, angio sarcoma, hepatocellularadenoma, and hemangioma.

Exemplary bone cancers include, for example, osteogenic sarcoma(osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cellsarcoma), multiple myeloma, malignant giant cell tumor chordoma,osteochronfroma (osteocartilaginous exostoses), benign chondroma,chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant celltumors

Exemplary nervous system cancers include cancers of the skull (osteoma,hemangioma, granuloma, xanthoma, osteitis deformans), meninges(meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma,meduoblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma,glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma,congenital tumors, neuro-ectodermal tumors), and spinal cord(neurofibroma, meningioma, glioma, sarcoma), neuroblastoma,Lhermitte-Duclos disease and pineal tumors.

Exemplary gynecological cancers include cancers of the breast (ductalcarcinoma, lobular carcinoma, breast sarcoma, triple-negative breastcancer, HER2-positive breast cancer, inflammatory breast cancer,papillary carcinoma), uterus (endometrial carcinoma), cervix (cervicalcarcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma(serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiedcarcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors,dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma,intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma),vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma(embryonal rhabdomyosarcoma), and fallopian tubes (carcinoma).

Exemplary skin cancers include melanoma, basal cell carcinoma, squamouscell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer, molesdysplastic nevi, lipoma, angioma, dermatofibroma, and keloids.

Exemplary head and neck cancers include glioblastoma, melanoma,rhabdosarcoma, lymphosarcoma, osteosarcoma, squamous cell carcinomas,adenocarcinomas, oral cancer, laryngeal cancer, nasopharyngeal cancer,nasal and paranasal cancers, thyroid and parathyroid cancers, tumors ofthe eye, tumors of the lips and mouth and squamous head and neck cancer.

The compounds of the present disclosure can also be useful in theinhibition of tumor metastases.

In addition to oncogenic neoplasms, the compounds of the invention areuseful in the treatment of skeletal and chondrocyte disorders including,but not limited to, achrondroplasia, hypochondroplasia, dwarfism,thanatophoric dysplasia (TD) (clinical forms TD I and TD II), Apertsyndrome, Crouzon syndrome, Jackson-Weiss syndrome, Beare-Stevensoncutis gyrate syndrome, Pfeiffer syndrome, and craniosynostosissyndromes. In some embodiments, the present disclosure provides a methodfor treating a patient suffering from a skeletal and chondrocytedisorder.

In some embodiments, compounds described herein can be used to treatAlzheimer's disease, HIV, or tuberculosis.

As used herein, the term “8p11 myeloproliferative syndrome” is meant torefer to myeloid/lymphoid neoplasms associated with eosinophilia andabnormalities of FGFR1.

As used herein, the term “cell” is meant to refer to a cell that is invitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can bepart of a tissue sample excised from an organism such as a mammal. Insome embodiments, an in vitro cell can be a cell in a cell culture. Insome embodiments, an in vivo cell is a cell living in an organism suchas a mammal.

As used herein, the term “contacting” refers to the bringing together ofindicated moieties in an in vitro system or an in vivo system. Forexample, “contacting” the FGFR enzyme with a compound described hereinincludes the administration of a compound described herein to anindividual or patient, such as a human, having FGFR, as well as, forexample, introducing a compound described herein into a samplecontaining a cellular or purified preparation containing the FGFRenzyme.

As used herein, the term “individual” or “patient,” usedinterchangeably, refers to any animal, including mammals, preferablymice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,horses, or primates, and most preferably humans.

As used herein, the phrase “therapeutically effective amount” refers tothe amount of active compound or pharmaceutical agent such as an amountof any of the solid forms or salts thereof as disclosed herein thatelicits the biological or medicinal response in a tissue, system,animal, individual or human that is being sought by a researcher,veterinarian, medical doctor or other clinician. An appropriate“effective” amount in any individual case may be determined usingtechniques known to a person skilled in the art.

The phrase “pharmaceutically acceptable” is used herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, immunogenicity or other problem orcomplication, commensurate with a reasonable benefit/risk ratio.

As used herein, the phrase “pharmaceutically acceptable carrier orexcipient” refers to a pharmaceutically-acceptable material,composition, or vehicle, such as a liquid or solid filler, diluent,solvent, or encapsulating material. Excipients or carriers are generallysafe, non-toxic and neither biologically nor otherwise undesirable andinclude excipients or carriers that are acceptable for veterinary use aswell as human pharmaceutical use. In one embodiment, each component is“pharmaceutically acceptable” as defined herein. See, e.g., Remington:The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams &Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients,6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the AmericanPharmaceutical Association: 2009; Handbook of Pharmaceutical Additives,3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007;Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRCPress LLC: Boca Raton, Fla., 2009.

As used herein, the term “treating” or “treatment” refers to inhibitingthe disease; for example, inhibiting a disease, condition or disorder inan individual who is experiencing or displaying the pathology orsymptomatology of the disease, condition or disorder (i.e. arrestingfurther development of the pathology and/or symptomatology) orameliorating the disease; for example, ameliorating a disease, conditionor disorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.reversing the pathology and/or symptomatology) such as decreasing theseverity of disease.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, can also beprovided in combination in a single embodiment (while the embodimentsare intended to be combined as if written in multiply dependent form).Conversely, various features of the invention which are, for brevity,described in the context of a single embodiment, can also be providedseparately or in any suitable subcombination.

Combination Therapy

One or more additional pharmaceutical agents or treatment methods suchas, for example, anti-viral agents, chemotherapeutics or otheranti-cancer agents, immune enhancers, immunosuppressants, radiation,anti-tumor and anti-viral vaccines, cytokine therapy (e.g., IL2, GM-CSF,etc.), and/or tyrosine kinase inhibitors can be used in combination withcompounds described herein for treatment of FGFR-associated diseases,disorders or conditions, or diseases or conditions as described herein.The agents can be combined with the present compounds in a single dosageform, or the agents can be administered simultaneously or sequentiallyas separate dosage forms.

Compounds described herein can be used in combination with one or moreother kinase inhibitors for the treatment of diseases, such as cancer,that are impacted by multiple signaling pathways. For example, acombination can include one or more inhibitors of the following kinasesfor the treatment of cancer: Akt1, Akt2, Akt3, TGF-βR, Pim, PKA, PKG,PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR,HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFαR, PDGFβR, CSFIR, KIT,FLK-II, KDR/FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron,Sea, TRKA, TRKB, TRKC, FLT3, VEGFR/Flt2, Flt4, EphA1, EphA2, EphA3,EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL,ALK and B-Raf. Additionally, the solid forms of the FGFR inhibitor asdescribed herein can be combined with inhibitors of kinases associatedwith the PIK3/Akt/mTOR signaling pathway, such as PI3K, Akt (includingAkt1, Akt2 and Akt3) and mTOR kinases.

In some embodiments, compounds described herein can be used incombination with one or more inhibitors of the enzyme or proteinreceptors such as HPK1, SBLB, TUT4, A2A/A2B, CD47, CDK2, STING, ALK2,LIN28, ADAR1, MAT2a, RIOK1, HDAC8, WDR5, SMARCA2, and DCLK1 for thetreatment of diseases and disorders. Exemplary diseases and disordersinclude cancer, infection, inflammation and neurodegenerative disorders.

In some embodiments, compounds described herein can be used incombination with a therapeutic agent that targets an epigeneticregulator. Examples of epigenetic regulators include bromodomaininhibitors, the histone lysine methyltransferases, histone argininemethyl transferases, histone demethylases, histone deacetylases, histoneacetylases, and DNA methyltransferases. Histone deacetylase inhibitorsinclude, e.g., vorinostat.

For treating cancer and other proliferative diseases, compoundsdescribed herein can be used in combination with targeted therapies,including JAK kinase inhibitors (Ruxolitinib, additional JAK1/2 andJAK1-selective, baricitinib or INCB39110), Pim kinase inhibitors (e.g.,LGH447, INCB053914 and SGI-1776), PI3 kinase inhibitors includingPI3K-delta selective and broad spectrum PI3K inhibitors (e.g., INCB50465and INCB54707), PI3K-gamma inhibitors such as PI3K-gamma selectiveinhibitors, MEK inhibitors, CSF1R inhibitors (e.g., PLX3397 andLY3022855), TAM receptor tyrosine kinases inhibitors (Tyro-3, Axl, andMer; e.g., INCB81776), angiogenesis inhibitors, interleukin receptorinhibitors, Cyclin Dependent kinase inhibitors, BRAF inhibitors, mTORinhibitors, proteasome inhibitors (Bortezomib, Carfilzomib),HDAC-inhibitors (panobinostat, vorinostat), DNA methyl transferaseinhibitors, dexamethasone, bromo and extra terminal family membersinhibitors (for example, bromodomain inhibitors or BET inhibitors, suchas OTX015, CPI-0610, INCB54329 or INCB57643), LSD1 inhibitors (e.g.,GSK2979552, INCB59872 and INCB60003), arginase inhibitors (e.g.,INCB1158), indoleamine 2,3-dioxygenase inhibitors (e.g., epacadostat,NLG919 or BMS-986205), PARP inhibiors (e.g., olaparib or rucaparib),inhibitors of BTK such as ibrutinib, c-MET inhibitors (e.g.,capmatinib), an ALK2 inhibitor (e.g., INCB00928); or combinationsthereof.

For treating cancer and other proliferative diseases, compoundsdescribed herein can be used in combination with chemotherapeuticagents, agonists or antagonists of nuclear receptors, or otheranti-proliferative agents. Compounds described herein can also be usedin combination with a medical therapy such as surgery or radiotherapy,e.g., gamma-radiation, neutron beam radiotherapy, electron beamradiotherapy, proton therapy, brachytherapy, and systemic radioactiveisotopes.

Examples of suitable chemotherapeutic agents include any of: abarelix,abiraterone, afatinib, aflibercept, aldesleukin, alemtuzumab,alitretinoin, allopurinol, altretamine, amidox, amsacrine, anastrozole,aphidicolon, arsenic trioxide, asparaginase, axitinib, azacitidine,bevacizumab, bexarotene, baricitinib, bendamustine, bicalutamide,bleomycin, bortezombi, bortezomib, brivanib, buparlisib, busulfanintravenous, busulfan oral, calusterone, camptosar, capecitabine,carboplatin, carmustine, cediranib, cetuximab, chlorambucil, cisplatin,cladribine, clofarabine, crizotinib, cyclophosphamide, cytarabine,dacarbazine, dacomitinib, dactinomycin, dalteparin sodium, dasatinib,dactinomycin, daunorubicin, decitabine, degarelix, denileukin,denileukin diftitox, deoxycoformycin, dexrazoxane, didox, docetaxel,doxorubicin, droloxafine, dromostanolone propionate, eculizumab,enzalutamide, epidophyllotoxin, epirubicin, epothilones, erlotinib,estramustine, etoposide phosphate, etoposide, exemestane, fentanylcitrate, filgrastim, floxuridine, fludarabine, fluorouracil, flutamide,fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelinacetate, histrelin acetate, ibritumomab tiuxetan, idarubicin,idelalisib, ifosfamide, imatinib mesylate, interferon alfa 2a,irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin,leuprolide acetate, levamisole, lonafarnib, lomustine, meclorethamine,megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen,mithramycin, mitomycin C, mitotane, mitoxantrone, nandrolonephenpropionate, navelbene, necitumumab, nelarabine, neratinib,nilotinib, nilutamide, niraparib, nofetumomab, oserelin, oxaliplatin,paclitaxel, pamidronate, panitumumab, panobinostat, pazopanib,pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin,pilaralisib, pipobroman, plicamycin, ponatinib, porfimer, prednisone,procarbazine, quinacrine, ranibizumab, rasburicase, regorafenib,reloxafine, revlimid, rituximab, rucaparib, ruxolitinib, sorafenib,streptozocin, sunitinib, sunitinib maleate, tamoxifen, tegafur,temozolomide, teniposide, testolactone, tezacitabine, thalidomide,thioguanine, thiotepa, tipifarnib, topotecan, toremifene, tositumomab,trastuzumab, tretinoin, triapine, trimidox, triptorelin, uracil mustard,valrubicin, vandetanib, vinblastine, vincristine, vindesine,vinorelbine, vorinostat, veliparib, talazoparib, and zoledronate.

Cancer cell growth and survival can be impacted by dysfunction inmultiple signaling pathways. Thus, it is useful to combine differentenzyme/protein/receptor inhibitors, exhibiting different preferences inthe targets which they modulate the activities of, to treat suchconditions. Targeting more than one signaling pathway (or more than onebiological molecule involved in a given signaling pathway) may reducethe likelihood of drug-resistance arising in a cell population, and/orreduce the toxicity of treatment.

One or more additional pharmaceutical agents such as, for example,chemotherapeutics, anti-inflammatory agents, steroids,immunosuppressants, immune-oncology agents, metabolic enzyme inhibitors,chemokine receptor inhibitors, and phosphatase inhibitors, as well astargeted therapies such as Bcr-Abl, Flt-3, EGFR, HER2, JAK, c-MET,VEGFR, PDGFR, c-Kit, IGF-1R, RAF, FAK, CDK2, and CDK4/6 kinaseinhibitors such as, for example, those described in WO 2006/056399 canbe used in combination with the treatment methods and regimens of thepresent disclosure for treatment of cancers and solid tumors. Otheragents such as therapeutic antibodies can be used in combination withthe treatment methods and regimens of the present disclosure fortreatment of cancers and solid tumors. The one or more additionalpharmaceutical agents can be administered to a patient simultaneously orsequentially.

The treatment methods as disclosed herein can be used in combinationwith one or more other enzyme/protein/receptor inhibitors therapies forthe treatment of diseases, such as cancer and other diseases ordisorders described herein. For example, the treatment methods andregimens of the present disclosure can be combined with one or moreinhibitors of the following kinases for the treatment of cancer: Akt1,Akt2, Akt3, BCL2, CDK2, CDK4/6, TGF-βR, PKA, PKG, PKC, CaM-kinase,phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4,INS-R, IDH2, IGF-1R, IR-R, PDGFαR, PDGFβR, PI3K (alpha, beta, gamma,delta, and multiple or selective), CSF1R, KIT, FLK-II, KDR/FLK-1, FLK-4,flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, PARP, Ron, Sea, TRKA, TRKB,TRKC, TAM kinases (Axl, Mer, Tyro3), FLT3, VEGFR/Flt2, Flt4, EphA1,EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK,FRK, JAK, ABL, ALK and B-Raf. Non-limiting examples of inhibitors thatcan be combined with the treatment methods and regimens of the presentdisclosure for treatment of cancer include an FGFR inhibitor (FGFR1,FGFR2, FGFR3 or FGFR4, e.g., pemigatinib (INCB54828), INCB62079), anEGFR inhibitor (also known as ErB-1 or HER-1; e.g. erlotinib, gefitinib,vandetanib, orsimertinib, cetuximab, necitumumab, or panitumumab), aVEGFR inhibitor or pathway blocker (e.g. bevacizumab, pazopanib,sunitinib, sorafenib, axitinib, regorafenib, ponatinib, cabozantinib,vandetanib, ramucirumab, lenvatinib, ziv-aflibercept), a PARP inhibitor(e.g. olaparib, rucaparib, veliparib or niraparib), a JAK inhibitor(JAK1 and/or JAK2, e.g., ruxolitinib, baricitinib, itacitinib(INCB39110), an LSD1 inhibitor (e.g., INCB59872 and INCB60003), a TDOinhibitor, a PI3K-delta inhibitor (e.g., INCB50465 and INCB50797), aPI3K-gamma inhibitor such as PI3K-gamma selective inhibitor, a Piminhibitor (e.g., INCB53914), a CSF1R inhibitor, a TAM receptor tyrosinekinases (Tyro-3, Axl, and Mer), an adenosine receptor antagonist (e.g.,A2a/A2b receptor antagonist), an HPK1 inhibitor, a chemokine receptorinhibitor (e.g. CCR2 or CCR5 inhibitor), a SHPT/2 phosphatase inhibitor,a histone deacetylase inhibitor (HDAC) such as an HDAC8 inhibitor, anangiogenesis inhibitor, an interleukin receptor inhibitor, bromo andextra terminal family members inhibitors (for example, bromodomaininhibitors or BET inhibitors such as INCB54329 and INCB57643), c-METinhibitors (e.g., capmatinib), an anti-CD19 antibody (e.g.,tafasitamab), an ALK2 inhibitor (e.g., INCB00928); or combinationsthereof.

In some embodiments, the treatment methods described herein are combinedwith administration of a PI3Kδ inhibitor. In some embodiments, thetreatment methods described herein are combined with administration of aJAK inhibitor. In some embodiments, the treatment methods describedherein are combined with administration of a JAK1 or JAK2 inhibitor(e.g., baricitinib or ruxolitinib). In some embodiments, the treatmentmethods described herein are combined with administration of a JAK1inhibitor. In some embodiments, the treatment methods described hereinare combined with administration of a JAK1 inhibitor, which is selectiveover JAK2.

Example antibodies that can be administered in combination therapyinclude, but are not limited to, trastuzumab (e.g., anti-HER2),ranibizumab (e.g., anti-VEGF-A), bevacizumab (AVASTIN™, e.g.,anti-VEGF), panitumumab (e.g., anti-EGFR), cetuximab (e.g., anti-EGFR),rituxan (e.g., anti-CD20), and antibodies directed to c-MET.

One or more of the following agents may be administered to a patient incombination with the treatment methods of the present disclosure and arepresented as a non-limiting list: a cytostatic agent, cisplatin,doxorubicin, taxotere, taxol, etoposide, irinotecan, camptostar,topotecan, paclitaxel, docetaxel, epothilones, tamoxifen,5-fluorouracil, methoxtrexate, temozolomide, cyclophosphamide, SCH66336, R115777, L778,123, BMS 214662, IRESSA™(gefitinib), TARCEVA™(erlotinib), antibodies to EGFR, intron, ara-C, adriamycin, cytoxan,gemcitabine, uracil mustard, chlormethine, ifosfamide, melphalan,chlorambucil, pipobroman, triethylenemelamine,triethylenethiophosphoramine, busulfan, carmustine, lomustine,streptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine,6-thioguanine, fludarabine phosphate, oxaliplatin, leucovirin, ELOXATIN™(oxaliplatin), pentostatine, vinblastine, vincristine, vindesine,bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin,idarubicin, mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase,teniposide 17.alpha.-ethinylestradiol, diethylstilbestrol, testosterone,Prednisone, Fluoxymesterone, Dromostanolone propionate, testolactone,megestrolacetate, methylprednisolone, methyltestosterone, prednisolone,triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide,estramustine, medroxyprogesteroneacetate, leuprolide, flutamide,toremifene, goserelin, carboplatin, hydroxyurea, amsacrine,procarbazine, mitotane, mitoxantrone, levamisole, navelbene,anastrazole, letrazole, capecitabine, reloxafine, droloxafine,hexamethylmelamine, avastin, HERCEPTIN™ (trastuzumab), BEXXAR™(tositumomab), VELCADE™ (bortezomib), ZEVALIN™ (ibritumomab tiuxetan),TRISENOX™ (arsenic trioxide), XELODA™ (capecitabine), vinorelbine,porfimer, ERBITUX™ (cetuximab), thiotepa, altretamine, melphalan,trastuzumab, lerozole, fulvestrant, exemestane, ifosfomide, rituximab,C225 (cetuximab), Campath (alemtuzumab), clofarabine, cladribine,aphidicolon, rituxan, sunitinib, dasatinib, tezacitabine, Sml1,fludarabine, pentostatin, triapine, didox, trimidox, amidox, 3-AP, andMDL-101,731.

The treatment methods and regimens of the present disclosure can furtherbe used in combination with other methods of treating cancers, forexample by chemotherapy, irradiation therapy, tumor-targeted therapy,adjuvant therapy, immunotherapy or surgery. Examples of immunotherapyinclude cytokine treatment (e.g., interferons, GM-CSF, G-CSF, IL-2),CRS-207 immunotherapy, cancer vaccine, monoclonal antibody, bispecificor multi-specific antibody, antibody drug conjugate, adoptive T celltransfer, Toll receptor agonists, RIG-I agonists, oncolytic virotherapyand immunomodulating small molecules, including thalidomide or JAK1/2inhibitor, PI3Kδ inhibitor and the like. The compounds can beadministered in combination with one or more anti-cancer drugs, such asa chemotherapeutic agent. Examples of chemotherapeutics include any of:abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol,altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine,bevacizumab, bexarotene, baricitinib, bleomycin, bortezomib, busulfanintravenous, busulfan oral, calusterone, capecitabine, carboplatin,carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine,cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparinsodium, dasatinib, daunorubicin, decitabine, denileukin, denileukindiftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolonepropionate, eculizumab, epacadostat, epirubicin, erlotinib,estramustine, etoposide phosphate, etoposide, exemestane, fentanylcitrate, filgrastim, floxuridine, fludarabine, fluorouracil,fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelinacetate, histrelin acetate, ibritumomab tiuxetan, idarubicin,ifosfamide, imatinib mesylate, interferon alfa 2a, irinotecan, lapatinibditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate,levamisole, lomustine, meclorethamine, megestrol acetate, melphalan,mercaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane,mitoxantrone, nandrolone phenpropionate, nelarabine, nofetumomab,oxaliplatin, paclitaxel, pamidronate, panitumumab, pegaspargase,pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin,procarbazine, quinacrine, rasburicase, rituximab, ruxolitinib,sorafenib, streptozocin, sunitinib, sunitinib maleate, tamoxifen,temozolomide, teniposide, testolactone, thalidomide, thioguanine,thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin,uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine,vorinostat, and zoledronate.

Additional examples of chemotherapeutics include proteosome inhibitors(e.g., bortezomib), thalidomide, revlimid, and DNA-damaging agents suchas melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide,carmustine, and the like.

Example steroids include corticosteroids such as dexamethasone orprednisone.

Example Bcr-Abl inhibitors include imatinib mesylate (GLEEVAC™),nilotinib, dasatinib, bosutinib, and ponatinib, and pharmaceuticallyacceptable salts. Other example suitable Bcr-Abl inhibitors include thecompounds, and pharmaceutically acceptable salts thereof, of the generaand species disclosed in U.S. Pat. No. 5,521,184, WO 04/005281, and U.S.Ser. No. 60/578,491.

Example suitable Flt-3 inhibitors include midostaurin, lestaurtinib,linifanib, sunitinib, sunitinib, maleate, sorafenib, quizartinib,crenolanib, pacritinib, tandutinib, PLX3397 and ASP2215, and theirpharmaceutically acceptable salts. Other example suitable Flt-3inhibitors include compounds, and their pharmaceutically acceptablesalts, as disclosed in WO 03/037347, WO 03/099771, and WO 04/046120.

Example suitable RAF inhibitors include dabrafenib, sorafenib, andvemurafenib, and their pharmaceutically acceptable salts. Other examplesuitable RAF inhibitors include compounds, and their pharmaceuticallyacceptable salts, as disclosed in WO 00/09495 and WO 05/028444.

Example suitable FAK inhibitors include VS-4718, VS-5095, VS-6062,VS-6063, BI853520, and GSK2256098, and their pharmaceutically acceptablesalts. Other example suitable FAK inhibitors include compounds, andtheir pharmaceutically acceptable salts, as disclosed in WO 04/080980,WO 04/056786, WO 03/024967, WO 01/064655, WO 00/053595, and WO01/014402.

Example suitable CDK4/6 inhibitors include palbociclib, ribociclib,trilaciclib, lerociclib, and abemaciclib, and their pharmaceuticallyacceptable salts. Other example suitable CDK4/6 inhibitors includecompounds, and their pharmaceutically acceptable salts, as disclosed inWO 09/085185, WO 12/129344, WO 11/101409, WO 03/062236, WO 10/075074,and WO 12/061156.

In some embodiments, the compounds of the disclosure can be used incombination with one or more other kinase inhibitors including imatinib,particularly for treating patients resistant to imatinib or other kinaseinhibitors.

In some embodiments, the treatment methods of the disclosure can be usedin combination with a chemotherapeutic in the treatment of cancer, andmay improve the treatment response as compared to the response to thechemotherapeutic agent alone, without exacerbation of its toxic effects.In some embodiments, the treatment methods of the disclosure can be usedin combination with a chemotherapeutic provided herein. For example,additional pharmaceutical agents used in the treatment of multiplemyeloma, can include, without limitation, melphalan, melphalan plusprednisone [MP], doxorubicin, dexamethasone, and Velcade (bortezomib).Further additional agents used in the treatment of multiple myelomainclude Bcr-Abl, Flt-3, RAF and FAK kinase inhibitors. In someembodiments, the agent is an alkylating agent, a proteasome inhibitor, acorticosteroid, or an immunomodulatory agent. Examples of an alkylatingagent include cyclophosphamide (CY), melphalan (MEL), and bendamustine.In some embodiments, the proteasome inhibitor is carfilzomib. In someembodiments, the corticosteroid is dexamethasone (DEX). In someembodiments, the immunomodulatory agent is lenalidomide (LEN) orpomalidomide (POM). Additive or synergistic effects are desirableoutcomes of combining treatment methods of the present disclosure withan additional agent.

The agents can be combined with Compound 1 and/or antibody that binds tohuman PD-1 or human PD-L1, or antigen-binding fragment thereof, of thepresent treatment methods in a single or continuous dosage form, or theagents can be administered simultaneously or sequentially as separatedosage forms.

In some embodiments, a corticosteroid such as dexamethasone isadministered to a patient in combination with the treatment methods ofthe disclosure where the dexamethasone is administered intermittently asopposed to continuously.

The treatment methods described herein can be combined with anotherimmunogenic agent, such as cancerous cells, purified tumor antigens(including recombinant proteins, peptides, and carbohydrate molecules),cells, and cells transfected with genes encoding immune stimulatingcytokines. Non-limiting examples of tumor vaccines that can be usedinclude peptides of melanoma antigens, such as peptides of gp100, MAGEantigens, Trp-2, MARTI and/or tyrosinase, or tumor cells transfected toexpress the cytokine GM-CSF.

The treatment methods described herein can be used in combination with avaccination protocol for the treatment of cancer. In some embodiments,the tumor cells are transduced to express GM-CSF. In some embodiments,tumor vaccines include the proteins from viruses implicated in humancancers such as Human Papilloma Viruses (HPV), Hepatitis Viruses (HBVand HCV) and Kaposi's Herpes Sarcoma Virus (KHSV). In some embodiments,the treatment methods and regimens of the present disclosure can be usedin combination with tumor specific antigen such as heat shock proteinsisolated from tumor tissue itself. In some embodiments, the treatmentmethods described herein can be combined with dendritic cellsimmunization to activate potent anti-tumor responses.

The treatment methods and regimens of the present disclosure can be usedin combination with bispecific macrocyclic peptides that target Fe alphaor Fe gamma receptor-expressing effectors cells to tumor cells. Thetreatment methods and regimens of the present disclosure can also becombined with macrocyclic peptides that activate host immuneresponsiveness.

In some further embodiments, the treatment methods of the disclosure arecombined with administration of other therapeutic agents to a patientprior to, during, and/or after a bone marrow transplant or stem celltransplant. The treatment methods and regimens of the present disclosurecan be used in combination with bone marrow transplant for the treatmentof a variety of tumors of hematopoietic origin.

When more than one pharmaceutical agents is administered to a patient,as discussed in any of the above embodiments, they can be administeredsimultaneously, separately, sequentially, or in combination (e.g., formore than two agents).

Methods for the safe and effective administration of most of thesechemotherapeutic agents are known to those skilled in the art. Inaddition, their administration is described in the standard literature.For example, the administration of many of the chemotherapeutic agentsis described in the “Physicians' Desk Reference” (PDR, e.g., 1996edition, Medical Economics Company, Montvale, N.J.), the disclosure ofwhich is incorporated herein by reference as if set forth in itsentirety.

In some embodiments, compounds described herein can be used incombination with immune checkpoint inhibitors. Exemplary immunecheckpoint inhibitors include inhibitors against immune checkpointmolecules such as CD27, CD28, CD40, CD122, CD96, CD73, CD47, OX40, GITR,CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, CD137 (also known as4-1BB), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3 (e.g., INCAGN2385),TIM3 (e.g., INCB2390), VISTA, PD-1, PD-L1 and PD-L2. In someembodiments, the immune checkpoint molecule is a stimulatory checkpointmolecule selected from CD27, CD28, CD40, ICOS, OX40 (e.g., INCAGN1949),GITR (e.g., INCAGN1876) and CD137. In some embodiments, the immunecheckpoint molecule is an inhibitory checkpoint molecule selected fromA2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, and VISTA.In some embodiments, the compounds provided herein can be used incombination with one or more agents selected from KIR inhibitors, TIGITinhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors and TGFRbeta inhibitors.

In some embodiments, the inhibitor of an immune checkpoint molecule is asmall molecule PD-L1 inhibitor. In some embodiments, the small moleculePD-L1 inhibitor has an IC50 less than 1 less than 100 nM, less than 10nM or less than 1 nM in a PD-L1 assay described in US Patent PublicationNos. US 20170107216, US 20170145025, US 20170174671, US 20170174679, US20170320875, US 20170342060, US 20170362253, and US 20180016260, each ofwhich is incorporated by reference in its entirety for all purposes.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In someembodiments, the anti-PD-1 monoclonal antibody is MGA012, nivolumab,pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001,ipilumimab or AMP-224. In some embodiments, the anti-PD-1 monoclonalantibody is nivolumab or pembrolizumab. In some embodiments, theanti-PD1 antibody is pembrolizumab. In some embodiments, the anti-PD1antibody is nivolumab. In some embodiments, the anti-PD-1 monoclonalantibody is MGA012 (retifanlimab). In some embodiments, the anti-PD1antibody is SHR-1210. Other anti-cancer agent(s) include antibodytherapeutics such as 4-1BB (e.g. urelumab, utomilumab.

In some embodiments, the compounds of the disclosure can be used incombination with INCB086550.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In someembodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736,MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments,the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In someembodiments, the anti-CTLA-4 antibody is ipilimumab, tremelimumab,AGEN1884, or CP-675,206.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments,the anti-LAG3 antibody is BMS-986016, LAG525, or INCAGN2385.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of TIM3, e.g., an anti-TIM3 antibody. In some embodiments,the anti-TIM3 antibody is INCAGN2390, MBG453, or TSR-022.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of GITR, e.g., an anti-GITR antibody. In some embodiments,the anti-GITR antibody is TRX518, MK-4166, INCAGN1876, MK-1248, AMG228,BMS-986156, GWN323, or MEDI1873.

In some embodiments, the inhibitor of an immune checkpoint molecule isan agonist of OX40, e.g., OX40 agonist antibody or OX40L fusion protein.In some embodiments, the anti-OX40 antibody is MEDI0562, MOXR-0916,PF-04518600, GSK3174998, or BMS-986178. In some embodiments, the OX40Lfusion protein is MEDI6383.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD20, e.g., an anti-CD20 antibody. In some embodiments,the anti-CD20 antibody is obinutuzumab or rituximab.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD19, e.g., an anti-CD19 antibody. In some embodiments,the anti-CD19 antibody is tafasitamab.

The compounds of the present disclosure can be used in combination withbispecific antibodies. In some embodiments, one of the domains of thebispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3,CD137, ICOS, CD3 or TGFβ receptor.

In some embodiments, the compounds of the disclosure can be used incombination with one or more metabolic enzyme inhibitors. In someembodiments, the metabolic enzyme inhibitor is an inhibitor of IDOL TDO,or arginase. Examples of IDO1 inhibitors include epacadostat, NLG919,BMS-986205, PF-06840003, IOM2983, RG-70099 and LY338196.

Compounds of the present disclosure can be used in combination with oneor more immune checkpoint inhibitors for the treatment of diseases, suchas cancer or infections.

Exemplary immune checkpoint inhibitors include inhibitors against immunecheckpoint molecules such as CBL-B, CD20, CD28, CD40, CD70, CD122, CD96,CD73, CD₄₇, CDK2, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM,arginase, HPK1, CD137 (also known as 4-1BB), ICOS, A2AR, B7-H3, B7-H4,BTLA, CTLA-4, LAG3, TIM3, TLR (TLR7/8), TIGIT, CD112R, VISTA, PD-1,PD-L1 and PD-L2. In some embodiments, the immune checkpoint molecule isa stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS,OX40, GITR and CD137. In some embodiments, the immune checkpointmolecule is an inhibitory checkpoint molecule selected from A2AR, B7-H3,B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, TIGIT, and VISTA. Insome embodiments, the compounds provided herein can be used incombination with one or more agents selected from KIR inhibitors, TIGITinhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors and TGFRbeta inhibitors.

In some embodiments, the compounds provided herein can be used incombination with one or more agonists of immune checkpoint molecules,e.g., OX40, CD27, GITR, and CD137 (also known as 4-1BB).

In some embodiments, the inhibitor of an immune checkpoint molecule isanti-PD1 antibody, anti-PD-L1 antibody, or anti-CTLA-4 antibody.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-1 or PD-L1, e.g., an anti-PD-1 or anti-PD-L1monoclonal antibody. In some embodiments, the anti-PD-1 or anti-PD-L1antibody is nivolumab, pembrolizumab, atezolizumab, durvalumab,avelumab, cemiplimab, atezolizumab, avelumab, tislelizumab,spartalizumab (PDR001), cetrelimab (JNJ-63723283), toripalimab (JS001),camrelizumab (SHR-1210), sintilimab (IBI308), AB122 (GLS-010), AMP-224,AMP-514/MEDI-0680, BMS936559, JTX-4014, BGB-108, SHR-1210, MEDI4736,FAZ053, BCD-100, KN035, CS1001, BAT1306, LZMO09, AK105, HLX10, SHR-1316,CBT-502 (TQB2450), A167 (KL-A167), STI-A101 (ZKAB001), CK-301, BGB-A333,MSB-2311, HLX20, TSR-042, or LY3300054. In some embodiments, theinhibitor of PD-1 or PD-L1 is one disclosed in U.S. Pat. Nos. 7,488,802,7,943,743, 8,008,449, 8,168,757, 8,217, 149, or 10,308,644; U.S. Publ.Nos. 2017/0145025, 2017/0174671, 2017/0174679, 2017/0320875,2017/0342060, 2017/0362253, 2018/0016260, 2018/0057486, 2018/0177784,2018/0177870, 2018/0179179, 2018/0179201, 2018/0179202, 2018/0273519,2019/0040082, 2019/0062345, 2019/0071439, 2019/0127467, 2019/0144439,2019/0202824, 2019/0225601, 2019/0300524, or 2019/0345170; or PCT Pub.Nos. WO 03042402, WO 2008156712, WO 2010089411, WO 2010036959, WO2011066342, WO 2011159877, WO 2011082400, or WO 2011161699, which areeach incorporated herein by reference in their entirety. In someembodiments, the inhibitor of PD-L1 is INCB086550.

In some embodiments, the antibody is an anti-PD-1 antibody, e.g., ananti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1antibody is nivolumab, pembrolizumab, cemiplimab, spartalizumab,camrelizumab, cetrelimab, toripalimab, sintilimab, AB122, AMP-224,JTX-4014, BGB-108, BCD-100, BAT1306, LZMO09, AK105, HLX10, or TSR-042.In some embodiments, the anti-PD-1 antibody is nivolumab, pembrolizumab,cemiplimab, spartalizumab, camrelizumab, cetrelimab, toripalimab, orsintilimab. In some embodiments, the anti-PD-1 antibody ispembrolizumab. In some embodiments, the anti-PD-1 antibody is nivolumab.In some embodiments, the anti-PD-1 antibody is cemiplimab. In someembodiments, the anti-PD-1 antibody is spartalizumab. In someembodiments, the anti-PD-1 antibody is camrelizumab. In someembodiments, the anti-PD-1 antibody is cetrelimab. In some embodiments,the anti-PD-1 antibody is toripalimab. In some embodiments, theanti-PD-1 antibody is sintilimab. In some embodiments, the anti-PD-1antibody is AB122. In some embodiments, the anti-PD-1 antibody isAMP-224. In some embodiments, the anti-PD-1 antibody is JTX-4014. Insome embodiments, the anti-PD-1 antibody is BGB-108. In someembodiments, the anti-PD-1 antibody is BCD-100. In some embodiments, theanti-PD-1 antibody is BAT1306. In some embodiments, the anti-PD-1antibody is LZMO09. In some embodiments, the anti-PD-1 antibody isAK105. In some embodiments, the anti-PD-1 antibody is HLX10. In someembodiments, the anti-PD-1 antibody is TSR-042. In some embodiments, theanti-PD-1 monoclonal antibody is nivolumab or pembrolizumab. In someembodiments, the anti-PD1 antibody is SHR-1210. Other anti-canceragent(s) include antibody therapeutics such as 4-1BB (e.g., urelumab,utomilumab). In some embodiments, the inhibitor of an immune checkpointmolecule is an inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonalantibody. In some embodiments, the anti-PD-L1 monoclonal antibody isatezolizumab, avelumab, durvalumab, tislelizumab, BMS-935559, MEDI4736,atezolizumab (MPDL3280A; also known as RG7446), avelumab (MSB0010718C),FAZ053, KN035, CS1001, SHR-1316, CBT-502, A167, STI-A101, CK-301,BGB-A333, MSB-2311, HLX20, or LY3300054. In some embodiments, theanti-PD-L1 antibody is atezolizumab, avelumab, durvalumab, ortislelizumab. In some embodiments, the anti-PD-L1 antibody isatezolizumab. In some embodiments, the anti-PD-L1 antibody is avelumab.In some embodiments, the anti-PD-L1 antibody is durvalumab. In someembodiments, the anti-PD-L1 antibody is tislelizumab. In someembodiments, the anti-PD-L1 antibody is BMS-935559. In some embodiments,the anti-PD-L1 antibody is MEDI4736. In some embodiments, the anti-PD-L1antibody is FAZ053. In some embodiments, the anti-PD-L1 antibody isKN035. In some embodiments, the anti-PD-L1 antibody is CS1001. In someembodiments, the anti-PD-L1 antibody is SHR-1316. In some embodiments,the anti-PD-L1 antibody is CBT-502. In some embodiments, the anti-PD-L1antibody is A167. In some embodiments, the anti-PD-L1 antibody isSTI-A101. In some embodiments, the anti-PD-L1 antibody is CK-301. Insome embodiments, the anti-PD-L1 antibody is BGB-A333. In someembodiments, the anti-PD-L1 antibody is MSB-2311. In some embodiments,the anti-PD-L1 antibody is HLX20. In some embodiments, the anti-PD-L1antibody is LY3300054.

In some embodiments, the inhibitor of an immune checkpoint molecule is asmall molecule that binds to PD-L1, or a pharmaceutically acceptablesalt thereof. In some embodiments, the inhibitor of an immune checkpointmolecule is a small molecule that binds to and internalizes PD-L1, or apharmaceutically acceptable salt thereof. In some embodiments, theinhibitor of an immune checkpoint molecule is a compound selected fromthose in US 2018/0179201, US 2018/0179197, US 2018/0179179, US2018/0179202, US 2018/0177784, US 2018/0177870, U.S. Ser. No. 16/369,654(filed Mar. 29, 2019), and U.S. Ser. No. 62/688,164, or apharmaceutically acceptable salt thereof, each of which is incorporatedherein by reference in its entirety.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of KIR, TIGIT, LAIR1, CD160, 2B4 and TGFR beta.

In some embodiments, the inhibitor is MCLA-145.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In someembodiments, the anti-CTLA-4 antibody is ipilimumab, tremelimumab,AGEN1884, or CP-675,206.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments,the anti-LAG3 antibody is BMS-986016, LAG525, INCAGN2385, or eftilagimodalpha (IMP321).

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD73. In some embodiments, the inhibitor of CD73 isoleclumab.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of TIGIT. In some embodiments, the inhibitor of TIGIT isOMP-31M32.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of VISTA. In some embodiments, the inhibitor of VISTA isJNJ-61610588 or CA-170.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of B7-H3. In some embodiments, the inhibitor of B7-H3 isenoblituzumab, MGD009, or 8H9.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of KIR. In some embodiments, the inhibitor of KIR islirilumab or IPH4102.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of A2aR. In some embodiments, the inhibitor of A2aR isCPI-444.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of TGF-beta. In some embodiments, the inhibitor of TGF-betais trabedersen, galusertinib, or M7824.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PI3K-gamma. In some embodiments, the inhibitor ofPI3K-gamma is IPI-549.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD47. In some embodiments, the inhibitor of CD47 isHu5F9-G4 or TTI-621.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD73. In some embodiments, the inhibitor of CD73 isMEDI9447.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD70. In some embodiments, the inhibitor of CD70 iscusatuzumab or BMS-936561.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of TIM3, e.g., an anti-TIM3 antibody. In some embodiments,the anti-TIM3 antibody is INCAGN2390, MBG453, or TSR-022.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD20, e.g., an anti-CD20 antibody. In some embodiments,the anti-CD20 antibody is obinutuzumab or rituximab.

In some embodiments, the agonist of an immune checkpoint molecule is anagonist of OX40, CD27, CD28, GITR, ICOS, CD40, TLR7/8, and CD137 (alsoknown as 4-1BB).

In some embodiments, the agonist of CD137 is urelumab. In someembodiments, the agonist of CD137 is utomilumab.

In some embodiments, the agonist of an immune checkpoint molecule is aninhibitor of GITR. In some embodiments, the agonist of GITR is TRX518,MK-4166, INCAGN1876, MK-1248, AMG228, BMS-986156, GWN323, MEDI1873, orMEDI6469. In some embodiments, the agonist of an immune checkpointmolecule is an agonist of OX40, e.g., OX40 agonist antibody or OX40Lfusion protein. In some embodiments, the anti-OX40 antibody isINCAGN01949, MEDI0562 (tavolimab), MOXR-0916, PF-04518600, GSK3174998,BMS-986178, or 9B12. In some embodiments, the OX40L fusion protein isMEDI6383.

In some embodiments, the agonist of an immune checkpoint molecule is anagonist of CD40. In some embodiments, the agonist of CD40 is CP-870893,ADC-1013, CDX-1140, SEA-CD40, R07009789, JNJ-64457107, APX-005M, or ChiLob 7/4.

In some embodiments, the agonist of an immune checkpoint molecule is anagonist of ICOS. In some embodiments, the agonist of ICOS isGSK-3359609, JTX-2011, or MEDI-570.

In some embodiments, the agonist of an immune checkpoint molecule is anagonist of CD28. In some embodiments, the agonist of CD28 istheralizumab.

In some embodiments, the agonist of an immune checkpoint molecule is anagonist of CD27. In some embodiments, the agonist of CD27 is varlilumab.

In some embodiments, the agonist of an immune checkpoint molecule is anagonist of TLR7/8. In some embodiments, the agonist of TLR7/8 isMEDI9197.

The compounds of the present disclosure can be used in combination withbispecific antibodies. In some embodiments, one of the domains of thebispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3,CD137, ICOS, CD3 or TGFβ receptor. In some embodiments, the bispecificantibody binds to PD-1 and PD-L1. In some embodiments, the bispecificantibody that binds to PD-1 and PD-L1 is MCLA-136. In some embodiments,the bispecific antibody binds to PD-L1 and CTLA-4. In some embodiments,the bispecific antibody that binds to PD-L1 and CTLA-4 is AK104.

In some embodiments, the compounds of the disclosure can be used incombination with one or more metabolic enzyme inhibitors. In someembodiments, the metabolic enzyme inhibitor is an inhibitor of IDOL TDO,or arginase. Examples of IDO1 inhibitors include epacadostat, NLG919,BMS-986205, PF-06840003, IOM2983, RG-70099 and LY338196. Inhibitors ofarginase inhibitors include INCB1158.

As provided throughout, the additional compounds, inhibitors, agents,etc. can be combined with the present compound in a single or continuousdosage form, or they can be administered simultaneously or sequentiallyas separate dosage forms.

In some embodiments, the compounds described herein can be used incombination with one or more agents for the treatment of diseases suchas cancer. In some embodiments, the agent is an alkylating agent, aproteasome inhibitor, a corticosteroid, or an immunomodulatory agent.Examples of an alkylating agent include cyclophosphamide (CY), melphalan(MEL), and bendamustine. In some embodiments, the proteasome inhibitoris carfilzomib. In some embodiments, the corticosteroid is dexamethasone(DEX). In some embodiments, the immunomodulatory agent is lenalidomide(LEN) or pomalidomide (POM).

Suitable antiviral agents contemplated for use in combination withcompounds of the present disclosure can comprise nucleoside andnucleotide reverse transcriptase inhibitors (NRTIs), non-nucleosidereverse transcriptase inhibitors (NNRTIs), protease inhibitors and otherantiviral drugs.

Example suitable NRTIs include zidovudine (AZT); didanosine (ddl);zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir(1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194);BCH-10652; emitricitabine [(−)-FTC]; beta-L-FD4 (also called beta-L-D4Cand named beta-L-2′,3′-dicleoxy-5-fluoro-cytidene); DAPD,((−)-beta-D-2,6,-diamino-purine dioxolane); and lodenosine (FddA).Typical suitable NNRTIs include nevirapine (BI-RG-587); delaviradine(BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442(1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione);and (+)-calanolide A (NSC-675451) and B. Typical suitable proteaseinhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538);indinavir (MK-639); nelfnavir (AG-1343); amprenavir (141W94); lasinavir(BMS-234475); DMP-450; BMS-2322623; ABT-378; and AG-1 549. Otherantiviral agents include hydroxyurea, ribavirin, IL-2, IL-12,pentafuside and Yissum Project No. 11607.

Suitable agents for use in combination with compounds described hereinfor the treatment of cancer include chemotherapeutic agents, targetedcancer therapies, immunotherapies or radiation therapy. Compoundsdescribed herein may be effective in combination with antihormonalagents for treatment of breast cancer and other tumors. Suitableexamples are anti-estrogen agents including but not limited to tamoxifenand toremifene, aromatase inhibitors including but not limited toletrozole, anastrozole, and exemestane, adrenocorticosteroids (e.g.prednisone), progestins (e.g. megastrol acetate), and estrogen receptorantagonists (e.g. fulvestrant). Suitable anti-hormone agents used fortreatment of prostate and other cancers may also be combined withcompounds described herein. These include anti-androgens including butnot limited to flutamide, bicalutamide, and nilutamide, luteinizinghormone-releasing hormone (LHRH) analogs including leuprolide,goserelin, triptorelin, and histrelin, LHRH antagonists (e.g.degarelix), androgen receptor blockers (e.g. enzalutamide) and agentsthat inhibit androgen production (e.g. abiraterone).

The compounds described herein may be combined with or in sequence withother agents against membrane receptor kinases especially for patientswho have developed primary or acquired resistance to the targetedtherapy. These therapeutic agents include inhibitors or antibodiesagainst EGFR, Her2, VEGFR, c-Met, Ret, IGFR1, or Flt-3 and againstcancer-associated fusion protein kinases such as Bcr-Abl and EML4-Alk.Inhibitors against EGFR include gefitinib and erlotinib, and inhibitorsagainst EGFR/Her2 include but are not limited to dacomitinib, afatinib,lapitinib and neratinib. Antibodies against the EGFR include but are notlimited to cetuximab, panitumumab and necitumumab. Inhibitors of c-Metmay be used in combination with FGFR inhibitors. These includeonartumzumab, tivantnib, and INC-280. Agents against Abl (or Bcr-Abl)include imatinib, dasatinib, nilotinib, and ponatinib and those againstAlk (or EML4-ALK) include crizotinib.

Angiogenesis inhibitors may be efficacious in some tumors in combinationwith FGFR inhibitors. These include antibodies against VEGF or VEGFR orkinase inhibitors of VEGFR. Antibodies or other therapeutic proteinsagainst VEGF include bevacizumab and aflibercept. Inhibitors of VEGFRkinases and other anti-angiogenesis inhibitors include but are notlimited to sunitinib, sorafenib, axitinib, cediranib, pazopanib,regorafenib, brivanib, and vandetanib

Activation of intracellular signaling pathways is frequent in cancer,and agents targeting components of these pathways have been combinedwith receptor targeting agents to enhance efficacy and reduceresistance. Examples of agents that may be combined with compoundsdescribed herein include inhibitors of the PI3K-AKT-mTOR pathway,inhibitors of the Raf-MAPK pathway, inhibitors of JAK-STAT pathway, andinhibitors of protein chaperones and cell cycle progression.

Agents against the PI3 kinase include but are not limited topilaralisib,idelalisib, buparlisib. Inhibitors of mTOR such as rapamycin, sirolimus,temsirolimus, and everolimus may be combined with FGFR inhibitors. Othersuitable examples include but are not limited to vemurafenib anddabrafenib (Raf inhibitors) and trametinib, selumetinib and GDC-0973(MEK inhibitors). Inhibitors of one or more JAKs (e.g., ruxolitinib,baricitinib, tofacitinib), Hsp90 (e.g., tanespimycin), cyclin dependentkinases (e.g., palbociclib), HDACs (e.g., panobinostat), PARP (e.g.,olaparib), and proteasomes (e.g., bortezomib, carfilzomib) can also becombined with compounds described herein. In some embodiments, the JAKinhibitor is selective for JAK1 over JAK2 and JAK3.

Other suitable agents for use in combination with compounds describedherein include chemotherapy combinations such as platinum-based doubletsused in lung cancer and other solid tumors (cisplatin or carboplatinplus gemcitabine; cisplatin or carboplatin plus docetaxel; cisplatin orcarboplatin plus paclitaxel; cisplatin or carboplatin plus pemetrexed)or gemcitabine plus paclitaxel bound particles (Abraxane®).

Suitable chemotherapeutic or other anti-cancer agents include, forexample, alkylating agents (including, without limitation, nitrogenmustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas andtriazenes) such as uracil mustard, chlormethine, cyclophosphamide(Cytoxan™), ifosfamide, melphalan, chlorambucil, pipobroman,triethylene-melamine, triethylenethiophosphoramine, busulfan,carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

Other suitable agents for use in combination with compounds describedherein include steroids including 17 alpha-ethinylestradiol,diethylstilbestrol, testosterone, prednisone, fluoxymesterone,methylprednisolone, methyltestosterone, prednisolone, triamcinolone,chlorotrianisene, hydroxyprogesterone, aminoglutethimide, andmedroxyprogesteroneacetate.

Other suitable agents for use in combination with compounds describedherein include: dacarbazine (DTIC), optionally, along with otherchemotherapy drugs such as carmustine (BCNU) and cisplatin; the“Dartmouth regimen,” which consists of DTIC, BCNU, cisplatin andtamoxifen; a combination of cisplatin, vinblastine, and DTIC; ortemozolomide. Compounds described herein may also be combined withimmunotherapy drugs, including cytokines such as interferon alpha,interleukin 2, and tumor necrosis factor (TNF) in.

Suitable chemotherapeutic or other anti-cancer agents include, forexample, antimetabolites (including, without limitation, folic acidantagonists, pyrimidine analogs, purine analogs and adenosine deaminaseinhibitors) such as methotrexate, 5-fluorouracil, floxuridine,cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate,pentostatine, and gemcitabine.

Suitable chemotherapeutic or other anti-cancer agents further include,for example, certain natural products and their derivatives (forexample, vinca alkaloids, antitumor antibiotics, enzymes, lymphokinesand epipodophyllotoxins) such as vinblastine, vincristine, vindesine,bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin,idarubicin, ara-C, paclitaxel (TAXOL™), mithramycin, deoxycoformycin,mitomycin-C, L-asparaginase, interferons (especially IFN-α), etoposide,and teniposide.

Other cytotoxic agents include navelbene, CPT-11, anastrazole,letrazole, capecitabine, reloxafine, cyclophosphamide, ifosamide, anddroloxafine.

Also suitable are cytotoxic agents such as epidophyllotoxin; anantineoplastic enzyme; a topoisomerase inhibitor; procarbazine;mitoxantrone; platinum coordination complexes such as cis-platin andcarboplatin; biological response modifiers; growth inhibitors;antihormonal therapeutic agents; leucovorin; tegafur; and haematopoieticgrowth factors.

Other anti-cancer agent(s) include antibody therapeutics such astrastuzumab (Herceptin), antibodies to costimulatory molecules such asCTLA-4, 4-1BB, PD-L1 and PD-1 antibodies, or antibodies to cytokines(IL-10, TGF-β, etc.).

Other anti-cancer agents also include those that block immune cellmigration such as antagonists to chemokine receptors, including CCR2 andCCR4.

Other anti-cancer agents also include those that augment the immunesystem such as adjuvants or adoptive T cell transfer.

Anti-cancer vaccines include dendritic cells, synthetic peptides, DNAvaccines and recombinant viruses. In some embodiments, tumor vaccinesinclude the proteins from viruses implicated in human cancers such asHuman Papilloma Viruses (HPV), Hepatitis Viruses (HBV and HCV) andKaposi's Herpes Sarcoma Virus (KHSV). Non-limiting examples of tumorvaccines that can be used include peptides of melanoma antigens, such aspeptides of gp100, MAGE antigens, Trp-2, MARTI and/or tyrosinase, ortumor cells transfected to express the cytokine GM-CSF.

The compounds of the present disclosure can be used in combination withbone marrow transplant for the treatment of a variety of tumors ofhematopoietic origin.

Methods for the safe and effective administration of most of thesechemotherapeutic agents are known to those skilled in the art. Inaddition, their administration is described in the standard literature.For example, the administration of many of the chemotherapeutic agentsis described in the “Physicians' Desk Reference” (PDR, e.g., 1996edition, Medical Economics Company, Montvale, N.J.), the disclosure ofwhich is incorporated herein by reference as if set forth in itsentirety.

As provided throughout, the additional compounds, inhibitors, agents,etc. can be combined with the present compound in a single or continuousdosage form, or they can be administered simultaneously or sequentiallyas separate dosage forms.

Pharmaceutical Formulations and Dosage Forms

When employed as pharmaceuticals, compounds described herein can beadministered in the form of pharmaceutical compositions which refers toa combination of one or more compounds described herein, and at leastone pharmaceutically acceptable carrier or excipient. These compositionscan be prepared in a manner well known in the pharmaceutical art, andcan be administered by a variety of routes, depending upon whether localor systemic treatment is desired and upon the area to be treated.Administration may be topical (including ophthalmic and to mucousmembranes including intranasal, vaginal and rectal delivery), pulmonary(e.g., by inhalation or insufflation of powders or aerosols, includingby nebulizer; intratracheal, intranasal, epidermal and transdermal),ocular, oral or parenteral. Methods for ocular delivery can includetopical administration (eye drops), subconjunctival, periocular orintravitreal injection or introduction by balloon catheter or ophthalmicinserts surgically placed in the conjunctival sac. Parenteraladministration includes intravenous, intraarterial, subcutaneous,intraperitoneal, or intramuscular injection or infusion; orintracranial, e.g., intrathecal or intraventricular, administration.Parenteral administration can be in the form of a single bolus dose, ormay be, for example, by a continuous perfusion pump. Pharmaceuticalcompositions and formulations for topical administration may includetransdermal patches, ointments, lotions, creams, gels, drops,suppositories, sprays, liquids and powders. Conventional pharmaceuticalcarriers, aqueous, powder or oily bases, thickeners and the like may benecessary or desirable.

This disclosure also includes pharmaceutical compositions which contain,as the active ingredient, one or more compounds described herein incombination with one or more pharmaceutically acceptable carriers orexcipients. In making the compositions described herein, the activeingredient is typically mixed with an excipient, diluted by an excipientor enclosed within such a carrier in the form of, for example, acapsule, sachet, paper, or other container. When the excipient serves asa diluent, it can be a solid, semi-solid, or liquid material, which actsas a vehicle, carrier or medium for the active ingredient. Thus, thecompositions can be in the form of tablets, pills, powders, lozenges,sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups,aerosols (as a solid or in a liquid medium), ointments containing, forexample, up to 10% by weight of the active compound, soft and hardgelatin capsules, suppositories, sterile injectable solutions, andsterile packaged powders. In some embodiments, the composition issuitable for topical administration.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g. about 40 mesh.

The compounds of the invention may be milled using known millingprocedures such as wet milling to obtain a particle size appropriate fortablet formation and for other formulation types. Finely divided(nanoparticulate) preparations of the compounds of the invention can beprepared by processes known in the art see, e.g., WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions described herein can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

In some embodiments, the pharmaceutical composition comprises silicifiedmicrocrystalline cellulose (SMCC) and at least one compound describedherein, or a pharmaceutically acceptable salt thereof. In someembodiments, the silicified microcrystalline cellulose comprises about98% microcrystalline cellulose and about 2% silicon dioxide w/w.

In some embodiments, the composition is a sustained release compositioncomprising at least one compound described herein, or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablecarrier or excipient. In some embodiments, the composition comprises atleast one compound described herein, or a pharmaceutically acceptablesalt thereof, and at least one component selected from microcrystallinecellulose, lactose monohydrate, hydroxypropyl methylcellulose andpolyethylene oxide. In some embodiments, the composition comprises atleast one compound described herein, or a pharmaceutically acceptablesalt thereof, and microcrystalline cellulose, lactose monohydrate andhydroxypropyl methylcellulose. In some embodiments, the compositioncomprises at least one compound described herein, or a pharmaceuticallyacceptable salt thereof, and microcrystalline cellulose, lactosemonohydrate and polyethylene oxide. In some embodiments, the compositionfurther comprises magnesium stearate or silicon dioxide. In someembodiments, the microcrystalline cellulose is Avicel PH102™. In someembodiments, the lactose monohydrate is Fast-flo 316™. In someembodiments, the hydroxypropyl methylcellulose is hydroxypropylmethylcellulose 2208 K4M (e.g., Methocel K4 M Premier™) and/orhydroxypropyl methylcellulose 2208 K100LV (e.g., Methocel KOOLV™). Insome embodiments, the polyethylene oxide is polyethylene oxide WSR 1105(e.g., Polyox WSR 1105™).

In some embodiments, a wet granulation process is used to produce thecomposition. In some embodiments, a dry granulation process is used toproduce the composition.

The compositions can be formulated in a unit dosage form, each dosagecontaining from, for example, about 5 mg to about 1000 mg, about 5 mg toabout 100 mg, about 100 mg to about 500 mg or about 10 to about 30 mg,of the active ingredient. In some embodiments, each dosage containsabout 10 mg of the active ingredient. In some embodiments, each dosagecontains about 50 mg of the active ingredient. In some embodiments, eachdosage contains about 25 mg of the active ingredient. The term “unitdosage forms” refers to physically discrete units suitable as unitarydosages for human subjects and other mammals, each unit containing apredetermined quantity of active material calculated to produce thedesired therapeutic effect, in association with a suitablepharmaceutical excipient.

The components used to formulate the pharmaceutical compositions are ofhigh purity and are substantially free of potentially harmfulcontaminants (e.g., at least National Food grade, generally at leastanalytical grade, and more typically at least pharmaceutical grade).Particularly for human consumption, the composition is preferablymanufactured or formulated under Good Manufacturing Practice standardsas defined in the applicable regulations of the U.S. Food and DrugAdministration. For example, suitable formulations may be sterile and/orsubstantially isotonic and/or in full compliance with all GoodManufacturing Practice regulations of the U.S.

Food and Drug Administration.

The active compound can be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

The therapeutic dosage of a compound of the present invention can varyaccording to, e.g., the particular use for which the treatment is made,the manner of administration of the compound, the health and conditionof the patient, and the judgment of the prescribing physician. Theproportion or concentration of a compound of the invention in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of the inventioncan be provided in an aqueous physiological buffer solution containingabout 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 ug/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpre-formulation composition containing a homogeneous mixture of one ormore compounds described herein. When referring to these pre-formulationcompositions as homogeneous, the active ingredient is typicallydispersed evenly throughout the composition so that the composition canbe readily subdivided into equally effective unit dosage forms such astablets, pills and capsules. This solid pre-formulation is thensubdivided into unit dosage forms of the type described above containingfrom, for example, 0.1 to about 500 mg of the active ingredient of thepresent disclosure.

The tablets or pills of the present disclosure can be coated orotherwise compounded to provide a dosage form affording the advantage ofprolonged action. For example, the tablet or pill can comprise an innerdosage and an outer dosage component, the latter being in the form of anenvelope over the former. The two components can be separated by anenteric layer which serves to resist disintegration in the stomach andpermit the inner component to pass intact into the duodenum or to bedelayed in release. A variety of materials can be used for such entericlayers or coatings, such materials including a number of polymeric acidsand mixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the compounds, or compositions as describedherein can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions in can be nebulized by use of inert gases. Nebulizedsolutions may be breathed directly from the nebulizing device or thenebulizing device can be attached to a face masks tent, or intermittentpositive pressure breathing machine. Solution, suspension, or powdercompositions can be administered orally or nasally from devices whichdeliver the formulation in an appropriate manner.

Topical formulations can contain one or more conventional carriers. Insome embodiments, ointments can contain water and one or morehydrophobic carriers selected from, e.g., liquid paraffin,polyoxyethylene alkyl ether, propylene glycol, white Vaseline, and thelike. Carrier compositions of creams can be based on water incombination with glycerol and one or more other components, e.g.,glycerinemonostearate, PEG-glycerinemonostearate and cetylstearylalcohol. Gels can be formulated using isopropyl alcohol and water,suitably in combination with other components such as, e.g., glycerol,hydroxyethyl cellulose, and the like. In some embodiments, topicalformulations contain at least about 0.1, at least about 0.25, at leastabout 0.5, at least about 1, at least about 2 or at least about 5 wt %of the compound of the invention. The topical formulations can besuitably packaged in tubes of, e.g., 100 g which are optionallyassociated with instructions for the treatment of the select indication,e.g., psoriasis or other skin condition.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of a compound of the present disclosure can varyaccording to, for example, the particular use for which the treatment ismade, the manner of administration of the compound, the health andcondition of the patient, and the judgment of the prescribing physician.The proportion or concentration of the compounds in a pharmaceuticalcomposition can vary depending upon a number of factors includingdosage, chemical characteristics (e.g., hydrophobicity), and the routeof administration. For example, compounds of the present disclosure canbe provided in an aqueous physiological buffer solution containing about0.1 to about 10% w/v of the compound for parenteral administration. Sometypical dose ranges are from about 1 μg/kg to about 1 g/kg of bodyweight per day. In some embodiments, the dose range is from about 0.01mg/kg to about 100 mg/kg of body weight per day. The dosage is likely todepend on such variables as the type and extent of progression of thedisease or disorder, the overall health status of the particularpatient, the relative biological efficacy of the compound selected,formulation of the excipient, and its route of administration. Effectivedoses can be extrapolated from dose-response curves derived from invitro or animal model test systems.

Compounds described herein can also be formulated in combination withone or more additional active ingredients, which can include anypharmaceutical agent such as anti-viral agents, vaccines, antibodies,immune enhancers, immune suppressants, anti-inflammatory agents and thelike.

Labeled Compounds and Assay Methods

Another aspect of the present invention relates to labeled compounds ofthe disclosure (radio-labeled, fluorescent-labeled, etc.) that would beuseful not only in imaging techniques but also in assays, both in vitroand in vivo, for localizing and quantitating FGFR3 protein in tissuesamples, including human, and for identifying FGFR3 ligands byinhibition binding of a labeled compound. Substitution of one or more ofthe atoms of the compounds of the present disclosure can also be usefulin generating differentiated ADME (Adsorption, Distribution, Metabolismand Excretion). Accordingly, the present invention includes FGFR bindingassays that contain such labeled or substituted compounds.

The present disclosure further includes isotopically-labeled compoundsof the disclosure. An “isotopically” or “radio-labeled” compound is acompound of the disclosure where one or more atoms are replaced orsubstituted by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number typically found in nature (i.e.,naturally occurring). Suitable radionuclides that may be incorporated incompounds of the present disclosure include but are not limited to ²H(also written as D for deuterium), ³H (also written as T for tritium)¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br,⁷⁶Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I. For example, one or more hydrogen atomsin a compound of the present disclosure can be replaced by deuteriumatoms (e.g., one or more hydrogen atoms of a C₁₋₆ alkyl group of Formula(I) can be optionally substituted with deuterium atoms, such as —CD₃being substituted for —CH₃). In some embodiments, alkyl groups inFormula (I) can be perdeuterated.

One or more constituent atoms of the compounds presented herein can bereplaced or substituted with isotopes of the atoms in natural ornon-natural abundance. In some embodiments, the compound includes atleast one deuterium atom. In some embodiments, the compound includes twoor more deuterium atoms. In some embodiments, the compound includes 1-2,1-3, 1-4, 1-5, or 1-6 deuterium atoms. In some embodiments, all of thehydrogen atoms in a compound can be replaced or substituted by deuteriumatoms.

Synthetic methods for including isotopes into organic compounds areknown in the art (Deuterium Labeling in Organic Chemistry by Alan F.Thomas (New York, N.Y., Appleton-Century-Crofts, 1971; The Renaissanceof H/D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and JochenZimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistryof Isotopic Labelling by James R. Hanson, Royal Society of Chemistry,2011). Isotopically labeled compounds can be used in various studiessuch as NMR spectroscopy, metabolism experiments, and/or assays.

Substitution with heavier isotopes, such as deuterium, may affordcertain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances. (seee.g., A. Kerekes et. al. J. Med. Chem. 2011, 54, 201-210; R. Xu et. al.J. Label Compd. Radiopharm. 2015, 58, 308-312). In particular,substitution at one or more metabolism sites may afford one or more ofthe therapeutic advantages.

The radionuclide that is incorporated in the instant radio-labeledcompounds will depend on the specific application of that radio-labeledcompound. For example, for in vitro adenosine receptor labeling andcompetition assays, compounds that incorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵I, ¹³¹Ior ³⁵S can be useful. For radio-imaging applications ¹¹C, ¹⁸F, ¹²⁵I,¹²³I, ¹²⁴I, ¹³¹I, ⁷⁵Br, ⁷⁶Br or ⁷⁷Br can be useful.

It is understood that a “radio-labeled” or “labeled compound” is acompound that has incorporated at least one radionuclide. In someembodiments, the radionuclide is selected from the group consisting of³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br.

The present disclosure can further include synthetic methods forincorporating radio-isotopes into compounds of the disclosure. Syntheticmethods for incorporating radio-isotopes into organic compounds are wellknown in the art, and an ordinary skill in the art will readilyrecognize the methods applicable for the compounds of disclosure.

A labeled compound of the invention can be used in a screening assay toidentify and/or evaluate compounds. For example, a newly synthesized oridentified compound (i.e., test compound) which is labeled can beevaluated for its ability to bind an FGFR3 protein by monitoring itsconcentration variation when contacting with the FGFR3, through trackingof the labeling. For example, a test compound (labeled) can be evaluatedfor its ability to reduce binding of another compound which is known tobind to a FGFR3 protein (i.e., standard compound). Accordingly, theability of a test compound to compete with the standard compound forbinding to the FGFR3 protein directly correlates to its bindingaffinity. Conversely, in some other screening assays, the standardcompound is labeled and test compounds are unlabeled. Accordingly, theconcentration of the labeled standard compound is monitored in order toevaluate the competition between the standard compound and the testcompound, and the relative binding affinity of the test compound is thusascertained.

Kits

The present invention also includes pharmaceutical kits useful, forexample, in the treatment or prevention of FGFR-associated diseases ordisorders, such as cancer and other diseases referred to herein whichinclude one or more containers containing a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of thedisclosure. Such kits can further include, if desired, one or more ofvarious conventional pharmaceutical kit components, such as, forexample, containers with one or more pharmaceutically acceptablecarriers, additional containers, etc., as will be readily apparent tothose skilled in the art. Instructions, either as inserts or as labels,indicating quantities of the components to be administered, guidelinesfor administration, and/or guidelines for mixing the components, canalso be included in the kit.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results. The compounds of the Examples were found to be inhibitorsof FGFR3 as described below.

EXAMPLES

Experimental procedures for compounds of the invention are providedbelow. Preparatory LC-MS purifications of some of the compounds preparedwere performed on Waters mass directed fractionation systems. The basicequipment setup, protocols, and control software for the operation ofthese systems have been described in detail in the literature. See e.g.“Two-Pump At Column Dilution Configuration for Preparative LC-MS”, K.Blom, J. Combi. Chem., 4, 295 (2002); “Optimizing Preparative LC-MSConfigurations and Methods for Parallel Synthesis Purification”, K.Blom, R. Sparks, J. Doughty, G. Everlof, T. Hague, A. Combs, J. Combi.Chem., 5, 670 (2003); and “Preparative LC-MS Purification: ImprovedCompound Specific Method Optimization”, K. Blom, B. Glass, R. Sparks, A.Combs, J. Combi. Chem., 6, 874-883 (2004). The compounds separated weretypically subjected to analytical liquid chromatography massspectrometry (LCMS) for purity analysis under the following conditions:Instrument; Agilent 1100 series, LC/MSD, Column: Waters Sunfire™ C₁₈ 5μm, 2.1×50 mm, Buffers: mobile phase A: 0.025% TFA in water and mobilephase B: acetonitrile; gradient 2% to 80% of B in 3 minutes with flowrate 2.0 mL/minute.

Some of the compounds prepared were also separated on a preparativescale by reverse-phase high performance liquid chromatography (RP-HPLC)with MS detector or flash chromatography (silica gel) as indicated inthe Examples. Typical preparative reverse-phase high performance liquidchromatography (RP-HPLC) column conditions are as follows:

pH=2 purifications: Waters Sunfire™ C₁₈ 5 μm, 19×100 mm column, elutingwith mobile phase A: 0.1% TFA (trifluoroacetic acid) in water and mobilephase B: acetonitrile; the flow rate was 30 mL/minute, the separatinggradient was optimized for each compound using the Compound SpecificMethod Optimization protocol as described in the literature [see“Preparative LCMS Purification: Improved Compound Specific MethodOptimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem.,6, 874-883 (2004)]. Typically, the flow rate used with the 30×100 mmcolumn was 60 mL/minute.

pH=10 purifications: Waters)(Bridge C₁₈ 5 μm, 19×100 mm column, elutingwith mobile phase A: 0.15% NH₄OH in water and mobile phase B:acetonitrile; the flow rate was 30 mL/minute, the separating gradientwas optimized for each compound using the Compound Specific MethodOptimization protocol as described in the literature [See “PreparativeLCMS Purification: Improved Compound Specific Method Optimization”, K.Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874-883 (2004)].Typically, the flow rate used with 30×100 mm column was 60 mL/minute.

Example 1.5-(2,3-Dimethylphenyl)-6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine

Step 1. 6-Bromo-1-trityl-1H-pyrazolo[4,3-b]pyridine

NaH (60% in mineral oil, 2.46 g, 61.6 mmol) was slowly added at 0° C. toa solution of 6-bromo-1H-pyrazolo[4,3-b]pyridine (10.16 g, 51.3 mmol) inDMF (70 ml). After stirring at r.t. for 20 min,(chloromethanetriyl)tribenzene (15.73 g, 56.4 mmol) was slowly added andthe reaction mixture was stirred at r.t. for 1 h. Then water was addedand the precipitated product was collected by filtration, washed withwater and air dried. It was used in the next step without furtherpurification. LC-MS calculated for C₂₅H₁₉BrN₃ (M+H)⁺: m/z=440.1 and442.1; found 440.0 and 442.0.

Step 2. 6-Methoxy-1-trityl-1H-pyrazolo[4,3-b]pyridine

A mixture of 6-bromo-1-trityl-1H-pyrazolo[4,3-b]pyridine (25.0 g, 56.8mmol), cesium carbonate (25.9 g, 79 mmol), methanol (6.89 ml, 170 mmol)and ^(t)BuXPhos Pd G3 (1.52 g, 1.7 mmol) in toluene (150 ml) was heatedat 80° C. for 1 h. After cooling to r.t., the reaction mixture wasfiltered, the solvent evaporated in vacuo and crude material waspurified by Biotage Isolera. LCMS calculated for C₂₆H₂₂N₃O (M+H)⁺:m/z=392.2; Found: 392.1.

Step 3. 6-Methoxy-1-trityl-1H-pyrazolo[4,3-b]pyridine 4-oxide

m-CPBA (14.5 g, 64.6 mmol) was slowly added at 0° C. to a solution of6-methoxy-1-trityl-1H-pyrazolo[4,3-b]pyridine (16.8 g, 43.0 mmol) in DCM(150 ml). After stirring at r.t. overnight, the reaction was quenchedwith Na₂S₂O₃ solution and 1M NaOH solution. After stirring at r.t. for30 min, the organic phase was separated and washed 3 times with 1M NaOHsolution and 2 times with brine solution. Then the organic phase wasdried over sodium sulfate, filtered and the solvent was removed invacuo. The resultant product was used in the next step without furtherpurification. LC-MS calculated for C₂₆H₂₂N₃O₂ (M+H)⁺: m/z=408.2; found408.2.

Step 4. 5-Chloro-6-methoxy-1-trityl-1H-pyrazolo[4,3-b]pyridine

A solution of oxalyl chloride (5.36 ml, 61.3 mmol) in DCM was slowlyadded at 0° C. to a solution of6-methoxy-1-trityl-1H-pyrazolo[4,3-b]pyridine 4-oxide (16.65 g, 40.9mmol) and DIPEA (14.27 ml, 82 mmol) in DCM (100 ml). After stirring at0° C. for 1 h, the reaction was diluted with DCM and carefully quenchedwith water. The organic phase was separated, washed 3 times with water,2 times with saturated NaHCO₃ solution, 2 times with brine and was driedover sodium sulfate. After removing the solvent in vacuo, the resultantproduct was used in the next step without further purification. LC-MScalculated for C₂₆H₂₁ClN₃O (M+H)⁺: m/z=426.1; found 426.2.

Step 5. 5-Chloro-6-methoxy-1H-pyrazolo[4,3-b]pyridine

TFA (29 ml, 376 mmol) and water (1.35 ml, 75 mmol) were added to asolution of 5-chloro-6-methoxy-1-trityl-1H-pyrazolo[4,3-b]pyridine (16g, 37.6 mmol) in DCM (75 ml). After stirring at r.t. for 30 min, CH₃CNand water were added and the DCM was evaporated in vacuo. Theprecipitated solid was filtered off. The reaction mixture was furtherdiluted with water and was washed 3 times with EtOAc/hexane 1:1 mixture.The water phase was separated and all solvents were removed in vacuo.The residue was redissolved in DCM and was neutralized with NaHCO₃solution. The organic phase was further washed 2 times with NaHCO₃solution, brine, and then dried over sodium sulfate. The solvent wasevaporated in vacuo. The resultant crude product was used in the nextstep without further purification. LC-MS calculated for C₇H₇ClN₃O(M+H)⁺: m/z=184.0; found 184.1.

Step 6. tert-Butyl5-chloro-3-iodo-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate

NIS (6.87 g, 30.6 mmol) was added to a solution of5-chloro-6-methoxy-1H-pyrazolo[4,3-b]pyridine (5.5 g, 30.0 mmol) in DMF(60 ml). After stirring at 60° C. for 2 h, the reaction mixture wascooled to r.t., and triethylamine (6.26 ml, 44.9 mmol) and Boc-anhydride(8.17 g, 37.4 mmol) were added. After additional stirring at r.t. for 1h, water was added and the precipitated product was collected byfiltration. The solid product was air dried and used in the next stepwithout further purification. LC-MS calculated for C₁₂H₁₄ClIN₃O₃ (M+H)⁺:m/z=410.0; found 410.1.

Step 7. tert-Butyl5-chloro-6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine-1-carboxylate

tert-Butyl5-chloro-3-iodo-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate (8.73g, 21.31 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(5.32 g, 25.6 mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (3.48 g, 4.26 mmol) andpotassium phosphate (6.79 g, 32.0 mmol) were placed in a flask and theflask was evacuated and backfilled with N₂ three times. Then 1,4-dioxane(150 ml) and water (15 ml) were added and the reaction was stirred at80° C. for 1 h. After cooling to r.t., water was added and the desiredproduct was extracted with EtOAc. The organic phase was washed withbrine, dried over sodium sulfate and the solvent was evaporated invacuo. Crude material was purified by Biotage Isolera. LCMS calculatedfor C₁₆H₁₉ClN₅O₃ (M+H)⁺: m/z=364.1; Found: 364.0.

Step 8.5-(2,3-Dimethylphenyl)-6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine

tert-Butyl5-chloro-6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine-1-carboxylate(8 mg, 0.022 mmol), (2,3-dimethylphenyl)boronic acid (4.95 mg, 0.033mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(1.7 mg, 2.2 μmol) and potassium phosphate (9.34 mg, 0.044 mmol) wereplaced in a vial and the vial was evacuated and backfilled with N₂ threetimes. After 1,4-dioxane (1 ml) and water (100 μl) were added, thereaction mixture was stirred at 100° C. for 1 h. Then the reaction wasfiltered, and the solvents were evaporated in vacuo. DCM (1 ml) and TFA(0.5 ml) were added and the reaction mixture was stirred at r.t. for 30min. It was then diluted with CH₃CN and water and purified withprep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). Theproduct was isolated as the TFA salt. LCMS calculated for C₁₉H₂₀N₅O(M+H)⁺: m/z=334.2; Found: 334.2. ¹H NMR (500 MHz, DMSO-d6) δ 8.27 (s,1H), 8.00 (s, 1H), 7.45 (s, 1H), 7.25-7.20 (m, 1H), 7.19-7.14 (t, J=7.5Hz, 1H), 7.12-7.09 (m, 1H), 3.89 (s, 3H), 3.82 (s, 3H), 2.31 (s, 3H),1.96 (s, 3H) ppm.

Example 2.5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine

This compound was prepared according to the procedures described inExample 1, using2-(2,3-dihydro-1H-inden-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneinstead of (2,3-dimethylphenyl)boronic acid as starting material. Theproduct was isolated as the TFA salt. LCMS calculated for C₂₀H₂₀N₅O(M+H)⁺: m/z=346.2; Found: 346.2. ¹H NMR (500 MHz, DMSO-d6) δ 8.34-8.29(s, 1H), 8.09-8.01 (s, 1H), 7.51-7.44 (s, 1H), 7.30-7.25 (m, 2H),7.25-7.19 (m, 1H), 3.94-3.90 (s, 3H), 3.90-3.84 (s, 3H), 2.99-2.91 (t,J=7.4 Hz, 2H), 2.85-2.75 (t, J=7.4 Hz, 2H), 2.02-1.91 (p, J=7.4 Hz, 2H)ppm.

Example 3.5-(2,3-Dimethylphenyl)-6-methoxy-3-(1-((1-methyl-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine

Step 1.5-(2,3-Dimethylphenyl)-6-methoxy-1-(4-methoxybenzyl)-3-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine

To a solution of5-(2,3-dimethylphenyl)-3-iodo-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine(Example 69, 100 mg, 0.2 mmol) in 1,4-dioxane (3 mL) and water (0.3 mL)were added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(118 mg, 0.4 mmol), potassium phosphate (128 mg, 0.6 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (1:1) (16mg, 0.02 mmol). The reaction was purged with N₂ and stirred at 80° C.for 2 h. After this time it was cooled to r.t. and diluted with EtOAc.It was then washed sequentially with water, sat. NaCl solution and driedover Na₂SO₄. The organic phases were filtered and concentrated todryness. The residue was purified by Biotage Isolera to afford thedesired product. LC-MS calculated for C₂₆H₂₆N₅O₂ (M+H)+: m/z=440.2;found 440.2.

Step 2.5-(2,3-Dimethylphenyl)-6-methoxy-3-(1-((1-methyl-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine

To a solution of5-(2,3-dimethylphenyl)-6-methoxy-1-(4-methoxybenzyl)-3-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine(90 mg, 0.2 mmol) in acetonitrile (3 mL) were added5-(chloromethyl)-1-methyl-1H-1,2,4-triazole (70 mg, 0.53 mmol) andcesium carbonate (400 mg, 1.23 mmol). The reaction was stirred at 80° C.for 12 h. After this time it was cooled to r.t. and diluted with EtOAc.It was then washed sequentially with water, sat. NaCl solution and driedover Na₂SO₄. The organic phases were filtered and concentrated todryness. The residue was dissolved in TFA (1 ml) and heated to 80° C.for 1 h. The reaction mixture was then diluted with MeOH and purified byprep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). Theproduct was isolated as the TFA salt. LC-MS calculated for C₂₂H₂₃N₈O(M+H)⁺: m/z=415.2; found 415.2. ¹H NMR (600 MHz, DMSO-d6) δ 8.55-8.45(s, 1H), 8.14-8.03 (s, 1H), 7.93-7.82 (s, 1H), 7.52-7.42 (s, 1H),7.25-7.21 (d, J=7.5 Hz, 1H), 7.19-7.14 (t, J=7.5 Hz, 1H), 7.13-7.08 (d,J=7.5 Hz, 1H), 5.75-5.60 (s, 2H), 3.91-3.86 (s, 2H), 3.86-3.76 (s, 3H),2.34-2.27 (s, 3H), 2.01-1.90 (s, 3H) ppm.

Example 4.5-(2,3-Dihydrobenzofuran-7-yl)-6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine

This compound was prepared according to the procedures described inExample 1, using (2,3-dihydrobenzofuran-7-yl)boronic acid instead of(2,3-dimethylphenyl)boronic acid as starting material. The product wasisolated as the TFA salt. LCMS calculated for C₁₉H₁₈N₅O₂ (M+H)⁺:m/z=348.1; Found: 348.1. ¹H NMR (500 MHz, DMSO-d6) δ 8.33-8.29 (s, 1H),8.06-8.02 (s, 1H), 7.45-7.40 (s, 1H), 7.31-7.25 (d, J=5.8 Hz, 1H),7.21-7.16 (d, J=6.3 Hz, 1H), 6.96-6.86 (t, J=7.5 Hz, 1H), 4.54-4.44 (t,J=8.7 Hz, 2H), 3.94-3.90 (s, 3H), 3.87-3.82 (s, 3H), 3.29-3.20 (t, J=8.7Hz, 2H) ppm.

Intermediate 1.2-(2-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetonitrile

To a mixture of4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2]bi[[1,3,2]dioxaborolanyl] (1.28 g,5.1 mmol), potassium acetate (0.57 g, 5.83 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (0.318 g, 0.389 mmol) under nitrogen wasadded a solution of 2-(3-iodo-2-methylphenyl)acetonitrile (1 g, 3.89mmol) in 1,4-dioxane (30 mL). The reaction mixture was stirred undernitrogen at 100° C. for 3 days. After cooling to room temperature, themixture was diluted with DCM and filtered. The filtrate was concentratedin vacuo and the resultant residue was purified by Biotage Isolera togive the desired product.

Example 5.2-(3-(6-Methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2-methylphenyl)acetonitrile

This compound was prepared according to the procedures described inExample 1, using2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetonitrile(Intermediate 1) instead of (2,3-dimethylphenyl)boronic acid as startingmaterial. The product was isolated as the TFA salt. LCMS calculated forC₂₀H₁₉N₆O (M+H)⁺: m/z=359.2; Found: 359.2. ¹H NMR (500 MHz, DMSO-d6) δ8.33-8.22 (s, 1H), 8.05-7.95 (s, 1H), 7.53-7.48 (s, 1H), 7.47-7.41 (d,J=6.8 Hz, 1H), 7.36-7.30 (t, J=7.6 Hz, 1H), 7.30-7.25 (d, J=6.2 Hz, 1H),4.13-4.05 (s, 2H), 3.92-3.87 (s, 3H), 3.85-3.80 (s, 3H), 2.08-2.01 (s,3H) ppm.

Intermediate 2.4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-ol

To a mixture of4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2]bi[[1,3,2]dioxaborolanyl] (626 mg,2.46 mmol), potassium acetate (322 mg, 3.29 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (201 mg, 0.246 mmol) under nitrogen was addeda solution of 4-bromo-2,3-dihydro-1H-inden-1-ol (350 mg, 1.643 mmol) in1,4-dioxane (15 mL). The reaction mixture was stirred under nitrogen at100° C. overnight. After cooling to room temperature, the mixture wasdiluted with DCM and filtered. The filtrate was concentrated in vacuoand the resultant residue was purified by Biotage Isolera to give thedesired product.

Example 6.1-(4-(5-(6-(Difluoromethoxy)-5-(2,3-dimethylphenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperazin-1-yl)ethan-1-one

Step 1. 1-Trityl-1H-pyrazolo[4,3-b]pyridin-6-ol

A mixture of 6-bromo-1-trityl-1H-pyrazolo[4,3-b]pyridine (Example 1,step 1; 20 g, 45.4 mmol), KOH (12.74 g, 227 mmol), and ^(t)BuXPhos Pd G3(0.727 g, 0.908 mmol) in 1,4-dioxane (100 mL) water (100 mL) was heatedat 100° C. for 3 h. After this time it was cooled to r.t., diluted withwater and extracted with EtOAc. The combined organic phases were washedwith sat. aq. NaCl, dried over Na₂SO₄, filtered and concentrated todryness. The crude material was used in next step without furtherpurification. LCMS calculated for C₂₅H₂₀N₃O (M+H)⁺: m/z=378.2; Found:378.1.

Step 2. 6-(Difluoromethoxy)-1-trityl-1H-pyrazolo[4,3-b]pyridine

To a mixture of 1-trityl-1H-pyrazolo[4,3-b]pyridin-6-ol (17 g, 45 mmol)and KOH (12.62 g, 225 mmol) in acetonitrile (100 mL) and water (10 mL)was added diethyl (bromodifluoromethyl)-phosphonate (16.02 ml, 90 mmol)at 0° C. After addition, the reaction was stirred at r.t. overnight.Water was then added and the product was extracted with EtOAc. Theorganic phase was washed with brine, dried over sodium sulfate and thesolvent was evaporated in vacuo. Crude material was purified by BiotageIsolera. LCMS calculated for C₂₆H₂₀F2N₃O (M+H)⁺: m/z=428.2; Found:428.2.

Step 3. 5-Chloro-6-(difluoromethoxy)-1-trityl-1H-pyrazolo[4,3-b]pyridine

3-Chlorobenzoperoxoic acid (7.64 g, 33.2 mmol) was slowly added at 0° C.to a solution of 6-(difluoromethoxy)-1-trityl-1H-pyrazolo[4,3-b]pyridine(7.1 g, 16.61 mmol) in DCM (100 mL). After stirring at r.t. overnight,the reaction was treated with Na₂S₂O₃ solution and 1M NaOH solution.After stirring at r.t. for 30 min, the organic phase was separated andwashed 3 times with 1M NaOH solution and 2 times with brine solution.The organic phase was dried over sodium sulfate, filtered and thesolvent was removed in vacuo.

The resultant product was dissolved in DCM (100 mL). To this solutionDIEA (7.25 ml, 41.5 mmol) and oxalyl chloride (2.91 ml, 33.2 mmol) wereadded sequentially at 0° C. The reaction mixture was allowed to warm tor.t. and stirred at this temperature overnight. The reaction mixture wasdiluted with DCM and carefully treated with water. The organic phase wasseparated, washed 3 times with water, 2 times with saturated NaHCO₃solution, 2 times with brine and dried over sodium sulfate. Afterremoving the solvent in vacuo, crude material was purified by BiotageIsolera. LCMS calculated for C₂₆H₁₉ClF₂N₃O (M+H)⁺: m/z=462.1; Found:462.1.

Step 4.6-(Difluoromethoxy)-5-(2,3-dimethylphenyl)-1H-pyrazolo[4,3-b]pyridine

5-Chloro-6-(difluoromethoxy)-1-trityl-1H-pyrazolo[4,3-b]pyridine (2.2 g,4.76 mmol), (2,3-dimethylphenyl)boronic acid (1.072 g, 7.14 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(0.38 g, 0.47 mmol) and K₃PO₄ (2.1 g, 9.53 mmol) were placed in a flaskand the flask was evacuated and backfilled with N₂ three times. After1,4-dioxane (20 mL) and water (2 mL) were added, the reaction mixturewas stirred at 100° C. for 1 h. After cooling to r.t., water was addedand the desired product was extracted with EtOAc. The organic phase waswashed with brine, dried over sodium sulfate and the solvent wasevaporated in vacuo.

Crude material was dissolved in TFA (2 mL), DCM (10 mL), and water (2mL). After stirring at r.t. for 30 min, CH₃CN and water were added andthe DCM was evaporated in vacuo. The precipitated solid was filteredoff. The reaction mixture was further diluted with water and washed 3times with EtOAc/hexane 1:1 mixture. The water phase was separated andall solvents were removed in vacuo. The residue was dissolved in DCM andneutralized with NaHCO₃ solution. The organic phase was washed 2 timeswith NaHCO₃ solution, 1 time with brine, dried over sodium sulfate andconcentrated in vacuo. The resultant crude product was used in the nextstep without further purification. LC-MS calculated for C₁₅H₁₄F₂N₃O(M+H)⁺: m/z=290.1; found 290.1.

Step 5.6-(Difluoromethoxy)-5-(2,3-dimethylphenyl)-3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine

1-Iodopyrrolidine-2,5-dione (1.5 g, 6.57 mmol) was added to a solutionof 6-(difluoromethoxy)-5-(2,3-dimethylphenyl)-1H-pyrazolo[4,3-b]pyridine(1.9 g, 6.57 mmol) in DMF (25 mL). After stirring at 80° C. for 1 h, thereaction mixture was cooled to r.t., and Cs₂CO₃ (5.35 g, 16.42 mmol) and1-(chloromethyl)-4-methoxybenzene (1.714 ml, 13.14 mmol) were added.After additional stirring at 80° C. for 1 h, water was added and thedesired product was extracted with EtOAc. The organic phase was washedwith brine, dried over sodium sulfate and the solvent was evaporated invacuo. Crude material was purified by Biotage Isolera. LCMS calculatedfor C₂₃H₂₁F₂IN₃O₂ (M+H)⁺: m/z=536.1; Found: 536.1.

Step 6.1-(4-(5-(6-(Difluoromethoxy)-5-(2,3-dimethylphenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperazin-1-yl)ethan-1-one

A solution of6-(difluoromethoxy)-5-(2,3-dimethylphenyl)-3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine(27 mg, 0.050 mmol),1-(4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazin-1-yl)ethan-1-one(56 mg, 0.17 mmol), Xphos Pd G2 (4 mg, 5 μmol), potassium phosphate (44mg, 0.21 mmol) in water (0.100 ml) and dioxane (1 ml) was heated to 80°C. for 2 h. After this time it was cooled to r.t., diluted with waterand extracted with EtOAc. The combined organic phases were washed withsat. aq. NaCl and dried over Na₂SO₄, then filtered and concentrated todryness. The residue was dissolved in triflic acid (0.5 mL). The mixturewas stirred at r.t. for 1 h, diluted with CH₃CN and purified byprep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). Theproduct was isolated as the TFA salt. LCMS calculated for C₂₆H₂₇F₂N₆O₂(M+H)+: m/z=493.2; found 493.3. ¹H NMR (500 MHz, DMSO-d6) δ 13.47 (s,1H), 9.16 (d, J=2.2 Hz, 1H), 8.50 (dd, J=9.0, 2.4 Hz, 1H), 7.91 (s, 1H),7.46-7.01 (m, 5H), 3.66-3.58 (m, 8H), 2.35 (s, 3H), 2.05 (s, 3H), 2.02(s, 3H) ppm.

Example 7 and Example 8.4-(6-Methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-1-ol,two enantiomers

tert-Butyl5-chloro-6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine-1-carboxylate(35 mg, 0.096 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-ol(32 mg, 0.12 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(15 mg, 0.02 mmol) and potassium phosphate (30 mg, 0.14 mmol) wereplaced in a vial and the vial was evacuated and backfilled with N₂ threetimes. After 1,4-dioxane (2 ml) and water (200 μl) were added, thereaction mixture was stirred at 100° C. for 1 h. After cooling to roomtemperature, the mixture was diluted with DCM and filtered. The filtratewas concentrated in vacuo and the resultant residue was purified byBiotage Isolera.

The purified material was redissolved in 1,4-dioxane (2 ml) and water (2ml). After addition of cesium carbonate (31.3 mg, 0.096 mmol) andmorpholine (0.3 ml) the reaction mixture was heated at 100° C. for 2 h.After cooling to room temperature, the mixture was diluted with DCMwashed with brine, dried over sodium sulfate and the solvents wereevaporated in vacuo.

Then, the two enantiomers were separated with chiral prep-HPLC(Phenomenex Lux 5 um Amylose-1, 21.2×250 mm, eluting with 25% EtOH inhexanes, at flow rate of 20 mL/min, t_(R, peak 1)=15.4 mint_(R, peak 2)=17.6 min). After the solvents were evaporated in vacuo,both enantiomers were purified by prep-LCMS (XBridge C18 column, elutingwith a gradient of acetonitrile/water containing 0.1% TFA, at flow rateof 60 mL/min). The products were isolated as TFA salts.

Example 7. Peak 1: LCMS calculated for C₂₀H₂₀N₅O₂ (M+H)⁺: m/z=362.2;Found: 362.2. ¹H NMR (500 MHz, DMSO-d6) δ 8.32-8.25 (s, 1H), 8.07-8.00(s, 1H), 7.49-7.44 (s, 1H), 7.41-7.38 (d, J=7.3 Hz, 1H), 7.38-7.35 (d,J=7.5 Hz, 1H), 7.33-7.28 (m, 1H), 5.18-5.09 (t, J=6.7 Hz, 1H), 3.95-3.88(s, 3H), 3.88-3.82 (s, 3H), 2.87-2.75 (m, 1H), 2.75-2.65 (m, 1H),2.35-2.28 (m, 1H), 1.83-1.68 (m, 1H) ppm.

Example 8. Peak 2: LCMS calculated for C₂₀H₂₀N₅O₂ (M+H)⁺: m/z=362.2;Found: 362.2. ¹H NMR (500 MHz, DMSO-d6) δ 8.33-8.28 (s, 1H), 8.06-8.02(s, 1H), 7.49-7.45 (s, 1H), 7.42-7.38 (d, J=7.2 Hz, 1H), 7.38-7.35 (m,1H), 7.33-7.28 (m, 1H), 5.19-5.07 (t, J=6.7 Hz, 1H), 3.93-3.89 (s, 3H),3.89-3.85 (s, 3H), 2.86-2.75 (m, 1H), 2.75-2.66 (m, 1H), 2.36-2.22 (m,1H), 1.82-1.67 (m, 1H) ppm.

Example 9.4-(6-Methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile

Methanesulfonyl chloride (5 mg, 0.04 mmol) was added to a solution oftriethylamine (6.04 μl, 0.043 mmol) and tert-butyl5-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)-6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine-1-carboxylate(Intermediate from Example 8, 10 mg, 0.022 mmol) in DCM (1 ml). Afterstirring at r.t. for 30 min, the reaction mixture was filtered through apad of silica gel, the filter was washed with DCM and methanol, theorganic fractions were combined and the solvent was evaporated in vacuo.The resultant residue was dissolved in DMF (1 ml), and potassium cyanide(2.82 mg, 0.043 mmol) and 18-crown-6 (11 mg, 0.043 mmol) were added. Thereaction mixture was stirred at 80° C. for 2 h before water was addedand the desired product was extracted with DCM. The organic phase waswashed with brine and the solvent was evaporated in vacuo. The resultantmaterial was dissolved in DCM (1 ml) and TFA (0.5 ml), and the reactionmixture was stirred at r.t. for 30 min. It was then diluted with CH₃CNand water and purified with prep-LCMS (XBridge C18 column, eluting witha gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min). The product was isolated as the TFA salt. LCMS calculated forC₂₁H₁₉N₆O (M+H)⁺: m/z=371.2; Found: 371.2.

Intermediate 3.4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-ol

This compound was prepared according to the procedures described inIntermediate 2, using 4-bromo-2,3-dihydro-1H-inden-2-ol instead of4-bromo-2,3-dihydro-1H-inden-1-ol as starting material.

Example 10.4-(6-Methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-2-ol

tert-Butyl5-chloro-6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine-1-carboxylate(35 mg, 0.096 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-ol(32 mg, 0.12 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(15 mg, 0.02 mmol) and potassium phosphate (30 mg, 0.14 mmol) wereplaced in a vial and the vial was evacuated and backfilled with N₂ threetimes. After 1,4-dioxane (2 ml) and water (200 μl) were added, thereaction mixture was stirred at 100° C. for 1 h. After cooling to roomtemperature, the mixture was diluted with DCM and filtered. The filtratewas concentrated in vacuo and the resultant residue was purified byBiotage Isolera.

The two enantiomers were separated with chiral prep-HPLC (Phenomenex LUXCellulose-1 Sum 21.2×250 mm, eluting with 20% IPA (containing 2 mM NH₃)in hexanes, at flow rate of 65 mL/min, t_(R, peak 1)=6.5 min,t_(R, peak 2)=7.5 min). Peak 2 was collected and the solvents wereevaporated in vacuo. The resultant material was redissolved in1,4-dioxane (2 ml) and water (2 ml). After addition of cesium carbonate(31.3 mg, 0.096 mmol) and morpholine (0.3 ml) the reaction mixture washeated at 100° C. for 2 h. After cooling to room temperature, themixture was diluted with CH₃CN and purified by prep-LCMS (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%TFA, at flow rate of 60 mL/min). The product was isolated as the TFAsalt. LCMS calculated for C₂₀H₂₀N₅O₂ (M+H)⁺: m/z=362.2; Found: 362.2. ¹HNMR (500 MHz, DMSO-d6) δ 8.35-8.29 (s, 1H), 8.08-8.03 (s, 1H), 7.48-7.45(s, 1H), 7.34-7.28 (d, J=7.2 Hz, 1H), 7.29-7.25 (m, 1H), 7.25-7.20 (m,1H), 4.52-4.45 (m, 1H), 3.94-3.90 (s, 3H), 3.89-3.84 (s, 3H), 3.21-3.11(dd, J=16.0, 6.0 Hz, 1H), 3.09-3.00 (dd, J=16.4, 5.9 Hz, 1H), 2.88-2.78(dd, J=16.0, 3.6 Hz, 1H), 2.71-2.64 (dd, J=16.4, 3.6 Hz, 1H) ppm.

Intermediate 4.(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)methanol

Step 1. (4-Bromo-2,3-dihydro-1H-inden-1-yl)methanol

A 1M THF solution of LiHMDS (29.6 ml, 29.6 mmol) was slowly added to asuspension of (methoxymethyl)triphenylphosphonium chloride (10.15 g,29.6 mmol) in THF (150 ml) at 0° C. After this solution was stirring at0° C. for 1 h, a solution of 4-bromo-2,3-dihydro-1H-inden-1-one (5.0 g,23.7 mmol) in THF (20 ml) was slowly added and the reaction mixture wasstirred at r.t. for 2 h. The reaction was then quenched with water andthe product was extracted with EtOAc. The combined organic phases werewashed with brine, dried over anhydrous Na₂SO₄ and concentrated. Thecrude product was purified by Biotage Isolera.

A 1M DCM solution of BBr₃ (21.2 ml, 21.2 mmol) was added to a solutionof the above purified material in DCM (50 ml) at −78° C. After stirringat that temperature for 1 h, the reaction was quenched with water andthe product was extracted with DCM. The organic phase was dried oversodium sulfate and the solvent was evaporated in vacuo. The crudeproduct was purified by Biotage Isolera.

NaBH₄ (0.630 g, 16.7 mmol) was added to a solution of the resultantabove material in a mixture of THF (15 ml) and MeOH (15 ml). After thereaction mixture was stirred at r.t. for 1 h, water was added. Thedesired product was extracted with EtOAc, the organic phase was washedwith brine, dried over sodium sulfate and the solvents were evaporatedin vacuo. The resultant crude product was used in the next step withoutfurther purification.

Step 2.(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)methanol

This compound was prepared according to the procedures described inIntermediate 2, using (4-bromo-2,3-dihydro-1H-inden-1-yl)methanolinstead of 4-bromo-2,3-dihydro-1H-inden-1-ol as starting material.

Example 11 and Example 12.(4-(6-Methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-1-yl)methanol,two enantiomers

These compounds were prepared according to the procedures described inExample 7, using(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)methanol(Intermediate 4) instead of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-olas starting material.

The two enantiomers were separated with chiral prep-HPLC (Phenomenex LuxSum Amylose-1, 21.2×250 mm, eluting with 60% EtOH in hexanes, at flowrate of 20 mL/min, t_(R, peak 1)=4.2 min t_(R, peak 2)=7.6 min). Afterthe solvents were evaporated in vacuo, both enantiomers were purified byprep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). Theproducts were isolated as TFA salts.

Example 11. Peak 1: LCMS calculated for C₂₁H₂₂N₅O₂ (M+H)⁺: m/z=376.2;Found: 376.2. ¹H NMR (500 MHz, DMSO-d6) δ 8.34-8.28 (s, 1H), 8.07-8.00(s, 1H), 7.49-7.45 (s, 1H), 7.36-7.34 (d, J=7.4 Hz, 1H), 7.31-7.28 (d,J=7.5 Hz, 1H), 7.27-7.20 (t, J=7.5 Hz, 1H), 3.95-3.89 (s, 3H), 3.89-3.84(s, 3H), 3.74-3.66 (dd, J=10.4, 5.8 Hz, 1H), 3.58-3.51 (dd, J=10.4, 7.3Hz, 1H), 3.34-3.20 (p, J=6.9 Hz, 1H), 2.83-2.74 (t, J=7.5 Hz, 2H),2.23-2.06 (dq, J=14.6, 7.3 Hz, 1H), 1.87-1.71 (dq, J=14.4, 7.6 Hz, 1H)ppm.

Example 12. Peak 2: LCMS calculated for C₂₁H₂₂N₅O₂ (M+H)⁺: m/z=376.2;Found: 376.2. ¹H NMR (500 MHz, DMSO-d6) δ 8.34-8.29 (s, 1H), 8.09-8.01(s, 1H), 7.48-7.44 (s, 1H), 7.37-7.34 (d, J=7.3 Hz, 1H), 7.32-7.27 (d,J=7.4 Hz, 1H), 7.25-7.20 (t, J=7.5 Hz, 1H), 3.94-3.87 (s, 3H), 3.88-3.83(s, 3H), 3.74-3.67 (dd, J=10.4, 5.8 Hz, 1H), 3.58-3.50 (dd, J=10.4, 7.3Hz, 1H), 3.35-3.23 (p, J=6.8 Hz, 1H), 2.86-2.68 (t, J=7.4 Hz, 2H),2.19-2.05 (dq, J=14.5, 7.2 Hz, 1H), 1.86-1.73 (m, 1H) ppm.

Intermediate 5.2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-ol

Step 1. 4-Bromo-2-fluoro-2,3-dihydro-1H-inden-1-ol

Selectfluor (671 mg, 1.9 mmol) was added to a solution of4-bromo-2,3-dihydro-1H-inden-1-one (200 mg, 0.948 mmol) in acetonitrile(15 ml). After the reaction mixture was stirred at reflux overnight, thesolvent was evaporated in vacuo and the crude material was purified byBiotage Isolera.

NaBH₄ (62 mg, 1.6 mmol) was added to a solution of the above purifiedmaterial in a mixture of THF (2 ml) and MeOH (2 ml). After the reactionmixture was stirred at r.t. for 1 h, water was added. The desiredproduct was extracted with EtOAc, the organic phase was washed withbrine, dried over sodium sulfate and the solvents were evaporated invacuo. The resultant crude product was used in the next step withoutfurther purification.

Step 2.2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-ol

This compound was prepared according to the procedures described inIntermediate 2, using 4-bromo-2-fluoro-2,3-dihydro-1H-inden-1-ol insteadof 4-bromo-2,3-dihydro-1H-inden-1-ol as starting material. Intermediate5 was isolated as a cis-isomer with only traces of trans isomer.

Example 13.2-Fluoro-4-(6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-1-ol

This compound was prepared according to the procedures described inExample 7, using2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-ol(Intermediate 5) instead of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-olas starting material.

The two enantiomers were separated with chiral prep-HPLC (Phenomenex LuxSum Amylose-1, 21.2×250 mm, eluting with 35% EtOH in hexanes, at flowrate of 20 mL/min, t_(R, peak 1)=7.8 min, t_(R, peak 2)=9.8 min). Peak 2was collected. After the solvents were evaporated in vacuo, the productwas purified by prep-LCMS (XBridge C18 column, eluting with a gradientof acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min).The product was isolated as the TFA salt. LCMS calculated forC₂₀H₁₉FN₅O₂, (M+H)⁺: m/z=380.2; Found: 380.2. ¹H NMR (500 MHz, DMSO-d6)δ 8.35-8.31 (s, 1H), 8.07-8.04 (s, 1H), 7.51-7.47 (s, 1H), 7.48-7.44 (m,1H), 7.43-7.34 (m, 2H), 5.28-5.13 (m, 1H), 5.13-5.07 (m, 1H), 3.94-3.89(s, 3H), 3.89 3.86 (s, 3H), 3.24-3.06 (ddd, J=35.5, 17.3, 4.1 Hz, 1H),2.97-2.86 (dd, J=22.2, 17.0 Hz, 1H) ppm. Single crystal x-ray wasperformed on Intermediate 5, which is a cis-isomer, and its absolutestereochemistry was determined, confirming the absolute stereochemistryof the title compound.

The preparation of tert-butyl5-chloro-6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine-1-carboxylate,which is used as a starting material in this Example, is describedbelow:

Step 1. 6-Bromo-1-trityl-1H-pyrazolo[4,3-b]pyridine

NaH (60% in mineral oil, 2.46 g, 61.6 mmol) was slowly added at 0° C. toa solution of 6-bromo-1H-pyrazolo[4,3-b]pyridine (10.16 g, 51.3 mmol) inDMF (70 ml). After stirring at r.t. for 20 min,(chloromethanetriyl)tribenzene (15.73 g, 56.4 mmol) was slowly added andthe reaction mixture was stirred at r.t. for 1 h. Then water was addedand the precipitated product was collected by filtration, washed withwater and air dried. It was used in the next step without furtherpurification. LC-MS calculated for C₂₅H₁₉BrN₃ (M+H)⁺: m/z=440.1 and442.1; found 440.0 and 442.0.

Step 2. 6-Methoxy-1-trityl-1H-pyrazolo[4,3-b]pyridine

A mixture of 6-bromo-1-trityl-1H-pyrazolo[4,3-b]pyridine (25.0 g, 56.8mmol), cesium carbonate (25.9 g, 79 mmol), methanol (6.89 ml, 170 mmol)and ^(t)BuXPhos Pd G3 (1.52 g, 1.7 mmol) in toluene (150 ml) was heatedat 80° C. for 1 h. After cooling to r.t., the reaction mixture wasfiltered, the solvent evaporated in vacuo and crude material waspurified by Biotage Isolera. LCMS calculated for C₂₆H₂₂N₃O (M+H)⁺:m/z=392.2; Found: 392.1.

Step 3. 6-Methoxy-1-trityl-1H-pyrazolo[4,3-b]pyridine 4-oxide

m-CPBA (14.5 g, 64.6 mmol) was slowly added at 0° C. to a solution of6-methoxy-1-trityl-1H-pyrazolo[4,3-b]pyridine (16.8 g, 43.0 mmol) in DCM(150 ml). After stirring at r.t. overnight, the reaction was quenchedwith Na₂S₂O₃ solution and 1M NaOH solution. After stirring at r.t. for30 min, the organic phase was separated and washed 3 times with 1M NaOHsolution and 2 times with brine solution. Then the organic phase wasdried over sodium sulfate, filtered and the solvent was removed invacuo. The resultant product was used in the next step without furtherpurification. LC-MS calculated for C₂₆H₂₂N₃O₂ (M+H)⁺: m/z=408.2; found408.2.

Step 4. 5-Chloro-6-methoxy-1-trityl-1H-pyrazolo[4,3-b]pyridine

A solution of oxalyl chloride (5.36 ml, 61.3 mmol) in DCM was slowlyadded at 0° C. to a solution of6-methoxy-1-trityl-1H-pyrazolo[4,3-b]pyridine 4-oxide (16.65 g, 40.9mmol) and DIPEA (14.27 ml, 82 mmol) in DCM (100 ml). After stirring at0° C. for 1 h, the reaction was diluted with DCM and carefully quenchedwith water. The organic phase was separated, washed 3 times with water,2 times with saturated NaHCO₃ solution, 2 times with brine and was driedover sodium sulfate. After removing the solvent in vacuo, the resultantproduct was used in the next step without further purification. LC-MScalculated for C₂₆H₂₁ClN₃O (M+H)⁺: m/z=426.1; found 426.2.

Step 5. 5-Chloro-6-methoxy-1H-pyrazolo[4,3-b]pyridine

TFA (29 ml, 376 mmol) and water (1.35 ml, 75 mmol) were added to asolution of 5-chloro-6-methoxy-1-trityl-1H-pyrazolo[4,3-b]pyridine (16g, 37.6 mmol) in DCM (75 ml). After stirring at r.t. for 30 min, CH₃CNand water were added and the DCM was evaporated in vacuo. Theprecipitated solid was filtered off. The reaction mixture was furtherdiluted with water and was washed 3 times with EtOAc/hexane 1:1 mixture.The water phase was separated and all solvents were removed in vacuo.The residue was redissolved in DCM and was neutralized with NaHCO₃solution. The organic phase was further washed 2 times with NaHCO₃solution, brine, and then dried over sodium sulfate. The solvent wasevaporated in vacuo. The resultant crude product was used in the nextstep without further purification. LC-MS calculated for C₇H₇ClN₃O(M+H)⁺: m/z=184.0; found 184.1.

Step 6. tert-Butyl5-chloro-3-iodo-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate

NIS (6.87 g, 30.6 mmol) was added to a solution of5-chloro-6-methoxy-1H-pyrazolo[4,3-b]pyridine (5.5 g, 30.0 mmol) in DMF(60 ml). After stirring at 60° C. for 2 h, the reaction mixture wascooled to r.t., and triethylamine (6.26 ml, 44.9 mmol) and Boc-anhydride(8.17 g, 37.4 mmol) were added. After additional stirring at r.t. for 1h, water was added and the precipitated product was collected byfiltration. The solid product was air dried and used in the next stepwithout further purification. LC-MS calculated for C₁₂H₁₄ClIN₃O₃ (M+H)⁺:m/z=410.0; found 410.1.

Step 7. tert-Butyl5-chloro-6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine-1-carboxylate

tert-Butyl5-chloro-3-iodo-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate (8.73g, 21.31 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(5.32 g, 25.6 mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (3.48 g, 4.26 mmol) andpotassium phosphate (6.79 g, 32.0 mmol) were placed in a flask and theflask was evacuated and backfilled with N₂ three times. Then 1,4-dioxane(150 ml) and water (15 ml) were added and the reaction was stirred at80° C. for 1 h. After cooling to r.t., water was added and the desiredproduct was extracted with EtOAc. The organic phase was washed withbrine, dried over sodium sulfate and the solvent was evaporated invacuo. Crude material was purified by Biotage Isolera. LCMS calculatedfor C₁₆H₁₉ClN₅O₃ (M+H)⁺: m/z=364.1; Found: 364.0.

Example 14.5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-3-(1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine

Step 1.5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1-trityl-1H-pyrazolo[4,3-b]pyridine

5-Chloro-6-methoxy-1-trityl-1H-pyrazolo[4,3-b]pyridine (Example 1, Step4, 0.50 g, 1.174 mmol),2-(2,3-dihydro-1H-inden-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(0.32 g, 1.31 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(102 mg, 0.13 mmol) and potassium phosphate (274 mg, 1.3 mmol) wereplaced in a vial and the vial was evacuated and backfilled with N₂ threetimes. After 1,4-dioxane (10 ml) and water (1 ml) were added, thereaction mixture was stirred at 80° C. for 2 hs. After cooling to r.t.,water was added and the desired product was extracted with EtOAc. Theorganic phase was washed with brine, dried over sodium sulfate and thesolvent was evaporated in vacuo. Crude material was purified by BiotageIsolera to give a white solid (0.59 g, 99%). LCMS calculated forC₃₅H₃₀N₃O (M+H)⁺: m/z=508.2; found 508.1.

Step 2.5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine

5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1-trityl-1H-pyrazolo[4,3-b]pyridine(0.58 g, 1.143 mmol) in a mixture of DCM (10 ml) and TFA (4 ml) wasstirred at r.t. for 1 h. The reaction was then concentrated in vacuo,dissolved in DCM and neutralized with NaHCO₃ solution. The organic phasewas separated, dried over sodium sulfate and concentrated in vacuo.Crude material was purified by Biotage Isolera to give a white solid(0.2 g, 66%). LCMS calculated for C₁₆H₁₆N₃O (M+H)⁺: m/z=266.1; found266.1.

Step 3. tert-Butyl5-(2,3-dihydro-1H-inden-4-yl)-3-iodo-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate

NIS (0.220 g, 0.978 mmol) was added to a solution of5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine (0.20g, 0.754 mmol) in DMF (10 ml). After stirring at 80° C. for 2 h, thereaction mixture was cooled to r.t., and triethylamine (0.3 ml, 2.2mmol) and Boc-anhydride (0.411 g, 1.885 mmol) were added. Afteradditional stirring at r.t. for 1 h, water was added and theprecipitated product was collected by filtration and air dried. Crudematerial was purified by Biotage Isolera to give a white solid (0.29 g,78%). LCMS calculated for C₂₁H₂₃IN₃O₃ (M+H)⁺: m/z=492.1; found 492.1.

Step 4.5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-3-(1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine

tert-Butyl5-(2,3-dihydro-1H-inden-4-yl)-3-iodo-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate(0.10 g, 0.204 mmol),(1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-1H-pyrazol-4-yl)boronic acid(0.114 g, 0.407 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(17 mg, 22 mop and potassium phosphate (40 mg, 0.18 mmol) were placed ina vial and the vial was evacuated and backfilled with N₂ three times.After 1,4-dioxane (3 ml) and water (300 μl) were added, the reactionmixture was stirred at 80° C. for 2 hs. The reaction was then filtered,and the solvents were evaporated in vacuo. 4N solution of HCl in dioxane(2 ml) was added to the resultant residue and the reaction mixture wasstirred at r.t. for 1 h. The mixture was then diluted with CH₃CN andwater and purified with prep-LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min). The product was isolated as the TFA salt. LCMS calculated forC₂₃H₂₅N₆O (M+H)⁺: m/z=401.1; Found: 401.1.

Example 15.5-(2,3-Dihydro-1H-inden-4-yl)-3-(1-(1-ethylpyrrolidin-3-yl)-1H-pyrazol-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine

Acetaldehyde (11 mg, 0.24 mmol) and sodium triacetoxyborohydride (25 mg,0.12 mmol) were added to a solution of5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-3-(1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine(25 mg, 0.062 mmol) and one drop of acetic acid in DCE (1 ml). Afterstirring at r.t. overnight, the reaction was then diluted with CH₃CN andwater and purified with prep-LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min). The product was isolated as the TFA salt. LCMS calculated forC₂₅H₂₉N₆O (M+H)⁺: m/z=429.1; Found: 429.1.

Example 16.3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)cyclobutanecarbonitrile

This compound was prepared according to the procedures described inExample 14, using3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrileinstead of(1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-1H-pyrazol-4-yl)boronic acidas starting material. The product was isolated as the TFA salt. LCMScalculated for C₂₄H₂₃N₆O (M+H)⁺: m/z=411.2; Found: 411.2. ¹H NMR (500MHz, DMSO-d6) δ 8.44-8.37 (s, 1H), 8.20-8.15 (s, 1H), 7.50-7.44 (s, 1H),7.32-7.27 (m, 2H), 7.25-7.20 (t, J=7.4 Hz, 1H), 5.39-5.27 (p, J=8.0 Hz,1H), 3.92-3.82 (s, 3H), 3.02-2.88 (m, 4H), 2.85-2.73 (m, 4H), 2.06-1.91(p, J=7.4 Hz, 3H) ppm.

Example 17.5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-3-(1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine

Step 1. tert-Butyl3-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate

This compound was prepared according to the procedures described inExample 14, using tert-butyl3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylateinstead of(1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-1H-pyrazol-4-yl)boronic acidas starting material. LCMS calculated for C₃₂H₃₉N₆O₅ (M+H)⁺: m/z=587.3;Found: 587.3.

Step 2.3-(1-(Azetidin-3-yl)-1H-pyrazol-4-yl)-5-(2,3-dihydro-M-inden-4-yl)-6-methoxy-M-pyrazolo[4,3-b]pyridine

A solution of tert-butyl3-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate(0.14 g, 0.239 mmol) in a mixture of DCM (2 ml) and TFA (2 ml) wasstirred at r.t. for 2 hs. The solvent was then evaporated in vacuo andthe crude product was directly used in the next step without furtherpurification. LCMS calculated for C₂₂H₂₃N₆O (M+H)⁺: m/z=387.2; Found:387.2.

Step 3.5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-3-(1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine

Formaldehyde solution (0.02 ml) and sodium triacetoxyborohydride (25 mg,0.12 mmol) were added to a solution of3-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine(24 mg, 0.062 mmol) and one drop of acetic acid in DCE (1 ml). Afterstirring at r.t. overnight, the reaction was then diluted with CH₃CN andwater and purified with prep-LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min). The product was isolated as the TFA salt. LCMS calculated forC₂₃H₂₅N₆O (M+H)⁺: m/z=401.2; Found: 401.2. ¹H NMR (500 MHz, DMSO-d6) δ12.97-12.91 (s, 1H), 8.50-8.39 (s, 1H), 8.16-8.10 (s, 1H), 7.51-7.45 (s,1H), 7.33-7.27 (m, 2H), 7.26-7.18 (m, 1H), 5.16-5.00 (dt, J=13.6, 6.7Hz, 1H), 3.90-3.83 (s, 3H), 3.75-3.65 (t, J=7.5 Hz, 2H), 3.45-3.36 (m,2H), 3.01-2.89 (t, J=7.3 Hz, 2H), 2.88-2.77 (t, J=7.4 Hz, 2H), 2.36-2.29(s, 3H), 2.03-1.90 (dt, J=14.8, 7.4 Hz, 2H) ppm.

Example 18.5-(2,3-Dihydro-1H-inden-4-yl)-3-(1-(1-ethylazetidin-3-yl)-1H-pyrazol-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine

This compound was prepared according to the procedures described inExample 17, using acetaldehyde instead of formaldehyde as startingmaterial. The product was isolated as the TFA salt. LCMS calculated forC₂₄H₂₇N₆O (M+H)⁺: m/z=415.2; Found: 415.2.

Example 19.4-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)-N,N-dimethylpiperidine-1-carboxamide

Step 1.5-(2,3-Dihydro-1H-inden-4-yl)-3-iodo-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine

1-(Chloromethyl)-4-methoxybenzene (0.149 g, 0.951 mmol) was added tomixture of5-(2,3-dihydro-1H-inden-4-yl)-3-iodo-6-methoxy-1H-pyrazolo[4,3-b]pyridine(Example 14, Step 3, 0.31 g, 0.792 mmol) and cesium carbonate (500 mg,1.54 mmol) in DMF (5 ml). After stirring at 80° C. for 1 h, the reactionwas diluted with DCM and washed with water and brine. The organic phasewas dried over sodium sulfate and the solvent was evaporated in vacuo.Crude material was purified by Biotage Isolera (0.40, 99%). LCMScalculated for C₂₄H₂₃IN₃O₂ (M+H)⁺: m/z=512.1; Found: 512.1.

Step 2.5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-3-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine

5-(2,3-Dihydro-1H-inden-4-yl)-3-iodo-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine(0.200 g, 0.391 mmol), tert-butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(0.177 g, 0.469 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(17 mg, 22 μmol) and potassium phosphate (100 mg, 0.44 mmol) were placedin a vial and the vial was evacuated and backfilled with N₂ three times.After 1,4-dioxane (3 ml) and water (300 μl) were added, the reactionmixture was stirred at 100° C. for 1 h. Then the reaction was filtered,and the solvents were evaporated in vacuo. After purification by BiotageIsolera, DCM (1 ml) and TFA (1 ml) were added to the purified materialand the reaction mixture was stirred at r.t. for 1 h. The reactionmixture was then diluted with DCM and neutralized with NaHCO₃ solution.

The product was extracted with DCM, and organic phase was dried oversodium sulfate and concentrated in vacuo. The resultant product was usedin the next step without further purification. LCMS calculated forC₃₂H₃₅N₆O₂ (M+H)⁺: m/z=535.2; Found: 535.2.

Step 3.4-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)-N,N-dimethylpiperidine-1-carboxamide

To a solution of5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-3-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine(10 mg, 0.019 mmol) in 1,4-dioxane (0.5 ml) and Et₃N (0.02 ml) was addeddimethylcarbamic chloride (10 mg, 0.094 mmol). After stirring at r.t.for 1 h, the reaction was concentrated in vacuo. TFA (1 ml) was added tothe crude material and the resultant solution was heated at 100° C. for2 hs. The reaction was then diluted with CH₃CN and water and purifiedwith prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). Theproduct was isolated as the TFA salt. LCMS calculated for C₂₇H₃₂N₇O₂(M+H)⁺: m/z=486.2; Found: 486.2.

Example 20. Methyl4-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

This compound was prepared according to the procedures described inExample 19, using methyl chloroformate instead of dimethylcarbamicchloride. The product was isolated as the TFA salt. LC-MS calculated forC₂₆H₂₉N₆O₃ (M+H)⁺: m/z=473.2; Found: 473.2.

Example 21. Methyl3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate

Step 1.3-(1-(Azetidin-3-yl)-1H-pyrazol-4-yl)-5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine

This compound was prepared according to the procedures described inExample 19, using tert-butyl3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylateinstead of tert-butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate.LC-MS calculated for C₃₀H₃₁N₆O₂ (M+H)⁺: m/z=507.2; found: 507.2.

Step 2. Methyl3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate

This compound was prepared according to the procedures described inExample 19, using3-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridineinstead of5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-3-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine,and using methyl chloroformate instead of dimethylcarbamic chloride. Theproduct was isolated as the TFA salt. LC-MS calculated for C₂₄H₂₅N₆O₃(M+H)⁺: m/z=445.1; found: 445.1.

Example 22.1-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)ethan-1-one

This compound was prepared according to the procedures described inExample 21, using acetyl chloride instead of methyl chloroformate. Theproduct was isolated as the TFA salt. LC-MS calculated for C₂₄H₂₅N₆O₂(M+H)⁺: m/z=429.1; found: 429.1.

Example 23.5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-3-(1-(1-(methylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine

This compound was prepared according to the procedures described inExample 21, using methane sulfonyl chloride instead of methylchloroformate. The product was isolated as the TFA salt. LC-MScalculated for C₂₃H₂₅N₆O₃S (M+H)⁺: m/z=465.1; found: 465.1.

Example 24.3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)-N,N-dimethylazetidine-1-carboxamide

This compound was prepared according to the procedures described inExample 21, using dimethylcarbamic chloride instead of methylchloroformate. The product was isolated as the TFA salt. LC-MScalculated for C₂₅H₂₈N₇O₂ (M+H)⁺: m/z=458.1; found: 458.1.

Example 25.Cyclopropyl(3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)methanone

This compound was prepared according to the procedures described inExample 21, using cyclopropanecarbonyl chloride instead of methylchloroformate. The product was isolated as the TFA salt. LC-MScalculated for C₂₆H₂₇N₆O₂ (M+H)⁺: m/z=455.1; found: 455.1. ¹H NMR (500MHz, DMSO-d6) δ 8.52-8.44 (s, 1H), 8.26-8.16 (s, 1H), 7.51-7.43 (s, 1H),7.31-7.25 (m, 2H), 7.25-7.18 (t, J=7.4 Hz, 1H), 5.52-5.41 (m, 1H),4.75-4.69 (m, 1H), 4.60-4.52 (m, 1H), 4.36-4.26 (t, J=9.1 Hz, 1H),4.21-4.11 (dd, J=10.1, 5.1 Hz, 1H), 3.90-3.84 (s, 3H), 3.01-2.93 (t,J=7.4 Hz, 2H), 2.85-2.77 (t, J=7.4 Hz, 2H), 2.03-1.90 (p, J=7.4 Hz, 2H),1.66-1.53 (m, 1H), 0.82-0.70 (m, 4H) ppm.

Example 26.5-(2,3-Dihydro-1H-inden-4-yl)-6-ethoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine

Step 1. 6-Ethoxy-1-trityl-1H-pyrazolo[4,3-b]pyridine

A mixture of 6-bromo-1-trityl-1H-pyrazolo[4,3-b]pyridine (2.5 g, 5.7mmol), cesium carbonate (2.6 g, 8 mmol), ethanol (0.7 ml, 12 mmol) and^(t)BuXPhos Pd G3 (0.15 g, 0.17 mmol) in toluene (30 ml) was heated at80° C. for 1 h. After cooling to r.t., the reaction mixture wasfiltered, solvent evaporated in vacuo and crude material was purified byBiotage Isolera. LC-MS calculated for C₂₇H₂₄N₃O (M+H)⁺: m/z=406.1; found406.1.

Step 2. 6-Ethoxy-1-trityl-1H-pyrazolo[4,3-b]pyridine 4-oxide

To a solution of 6-ethoxy-1-trityl-1H-pyrazolo[4,3-b]pyridine (1.08 g,2.66 mmol) in 10 mL of DCM at 0° C. was added 3-chlorobenzoperoxoic acid(1.5 g, 6.52 mmol). The reaction was stirred at r.t. for 2 hrs. Thereaction mixture was diluted with DCM and the organic phase was washedwith Na₂S₂O₃ solution, followed by NaHCO₃ solution. After the solventwas concentrated in vacuo, the crude material was purified by BiotageIsolera to give a white solid (0.80 g, 71%). LC-MS calculated forC₂₇H₂₄N₃O₂ (M+H)⁺: m/z=422.1; found 422.1.

Step 3. 5-Chloro-6-ethoxy-1-trityl-1H-pyrazolo[4,3-b]pyridine

To a solution of 6-ethoxy-1-trityl-1H-pyrazolo[4,3-b]pyridine 4-oxide(0.80 g, 1.9 mmol) in 20 ml of DCM was added 1.0 ml of Et₃N. The mixturewas cooled to 0° C. in an ice bath, and oxalyl chloride (0.60 g, 4.7mmol) was slowly added. The reaction mixture was stirred at 0° C. for 1hr, before being neutralized with NaHCO₃ solution. The organic phase wasseparated, dried over sodium sulfate and concentrated in vacuo. Thecrude material was purified by Biotage Isolera to give a white solid(0.26 g, 31%). LC-MS calculated for C₂₇H₂₃ClN₃O (M+H)⁺: m/z=440.2; found440.2.

Step 4.5-(2,3-Dihydro-1H-inden-4-yl)-6-ethoxy-1H-pyrazolo[4,3-b]pyridine

This compound was prepared according to the procedures described inExample 14, using 5-chloro-6-ethoxy-1-trityl-1H-pyrazolo[4,3-b]pyridineinstead of 5-chloro-6-methoxy-1-trityl-1H-pyrazolo[4,3-b]pyridine. LC-MScalculated for C₁₇H₁₈N₃O (M+H)⁺: m/z=280.1; found 280.1.

Step 5. tert-Butyl5-(2,3-dihydro-1H-inden-4-yl)-6-ethoxy-3-iodo-1H-pyrazolo[4,3-b]pyridine-1-carboxylate

This compound was prepared according to the procedures described inExample 21, step 2, using5-(2,3-dihydro-1H-inden-4-yl)-6-ethoxy-1H-pyrazolo[4,3-b]pyridineinstead of5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine.LC-MS calculated for C₂₂H₂₅IN₃O₃ (M+H)⁺: m/z=506.1; found 506.1.

Step 6.5-(2,3-Dihydro-1H-inden-4-yl)-6-ethoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine

A mixture of1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (20mg, 0.096 mmol), tert-butyl5-(2,3-dihydro-1H-inden-4-yl)-6-ethoxy-3-iodo-1H-pyrazolo[4,3-b]pyridine-1-carboxylate(7 mg, 0.014 mmol), X-Phos Pd G2 (4 mg, 0.001 mmol) and K₃PO₄ (10 mg,0.05 mmol) was combined with dioxane (1 ml) and water (0.1 ml) and thereaction mixture was heated at 80° C. for 2 hrs. After cooling to r.t.,the reaction was filtered and 2 mL of 4N HCl in dioxane was added. Thereaction mixture was stirred at r.t. for an additional 1 hr before itwas concentrated in vacuo. The residue was then dissolved in a mixtureof CH₃CN and water, and the product was purified with prep-LCMS (XBridgeC18 column, eluting with a gradient of acetonitrile/water containing0.1% TFA, at flow rate of 60 mL/min). The product was isolated as theTFA salt. LC-MS calculated for C₂₁H₂₂N₅O (M+H)⁺: m/z=360.1; found:360.1.

Example 27.5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-3-(1-(pyridin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine

This compound was prepared according to the procedures described inExample 14, using4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)pyridineinstead of(1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-1H-pyrazol-4-yl)boronic acidas starting material. The product was isolated as the TFA salt. LC-MScalculated for C₂₅H₂₃N₆O (M+H)⁺: m/z=423.1; found: 423.1.

Example 28.4-(2-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)ethyl)morpholine

This compound was prepared according to the procedures described inExample 14, using4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)morpholineinstead of(1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-1H-pyrazol-4-yl)boronic acidas starting material. The product was isolated as the TFA salt. LC-MScalculated for C₂₅H₂₉N₆O₂ (M+H)⁺: m/z=445.1; found: 445.1.

Example 29.3-(1-Cyclopropyl-1H-pyrazol-4-yl)-5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine

This compound was prepared according to the procedures described inExample 14, using1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleinstead of(1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-1H-pyrazol-4-yl)boronic acidas starting material. The product was isolated as the TFA salt. LC-MScalculated for C₂₂H₂₂N₅O (M+H)⁺: m/z=372.1; found: 372.1.

Example 30.3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)propanenitrile

This compound was prepared according to the procedures described inExample 14, using3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanenitrileinstead of(1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-1H-pyrazol-4-yl)boronic acidas starting material. The product was isolated as the TFA salt. LC-MScalculated for C₂₂H₂₁N₆O (M+H)⁺: m/z=385.1; found: 385.1.

Example 31.2-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)ethan-1-ol

This compound was prepared according to the procedures described inExample 14, using2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-olinstead of(1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-1H-pyrazol-4-yl)boronic acidas starting material. The product was isolated as the TFA salt. LC-MScalculated for C₂₁H₂₂N₅O₂ (M+H)⁺: m/z=376.1; found: 376.1. ¹H NMR (500MHz, DMSO-d6) δ 8.38-8.30 (s, 1H), 8.11-8.04 (s, 1H), 7.50-7.42 (s, 1H),7.33-7.26 (m, 2H), 7.25-7.17 (m, 1H), 4.29-4.17 (t, J=5.5 Hz, 2H),3.92-3.83 (s, 3H), 3.79-3.73 (t, J=5.5 Hz, 2H), 3.00-2.91 (t, J=7.3 Hz,2H), 2.84-2.78 (t, J=7.4 Hz, 2H), 2.07-1.92 (p, J=7.5 Hz, 2H) ppm.

Example 32.5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-3-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine

This compound was prepared according to the procedures described inExample 14, using4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)pyridine instead of(1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-1H-pyrazol-4-yl)boronic acidas starting material. The product was isolated as the TFA salt. LC-MScalculated for C₂₄H₂₁N₆O (M+H)⁺: m/z=409.1; found: 409.1.

Example 33.(trans)-4-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)cyclohexan-1-ol

This compound was prepared according to the procedures described inExample 14, using((trans)-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleinstead of(1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-1H-pyrazol-4-yl)boronic acidas starting material. The product was isolated as the TFA salt. LC-MScalculated for C₂₅H₂₈N₅O₂ (M+H)⁺: m/z=430.1; found: 430.1.

Example 34.5-(2,3-Dimethylphenyl)-N-methyl-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-6-amine

Step 1. 6-Bromo-3-iodo-1H-pyrazolo[4,3-b]pyridine

To a solution of 6-bromo-1H-pyrazolo[4,3-b]pyridine (8.0 g, 40.4 mmol)in 60 ml of DMF was added 1-iodopyrrolidine-2,5-dione (7.69 g, 44.4mmol), and the reaction mixture was stirred at r.t for 2 h. The mixturewas poured into water (300 ml) and was stirred for another 10 min. Theresulting solid was collected by filtration and was washed with water.It was air-dried and used in the next step without further purification.LC-MS calculated for C₆H₄BrIN₃ (M+H)⁺: m/z=323.9; found 323.9.

Step 2. 6-Bromo-3-iodo-1-trityl-1H-pyrazolo[4,3-b]pyridine

To a suspension of NaH (1.63 g, 40.8 mmol) in DMF (100 ml) at 0° C. wasadded a solution of 6-bromo-3-iodo-1H-pyrazolo[4,3-b]pyridine (12.0 g,37.0 mmol) in 20 ml of DMF dropwise. After the addition was complete,the reaction mixture was warmed to r.t and stirred at that temperaturefor 30 min. The mixture was then cooled back to 0° C. and treated with asolution of (chloromethanetriyl)tribenzene (11.4 g, 40.8 mmol) in 20 mlof DMF. The reaction mixture was stirred at r.t for 2 h. Water was thenadded and the product was extracted with DCM. The organic phase wasconcentrated in vacuo. The resultant solid was collected by filtrationand air-dried. LC-MS calculated for C₂₅H₁₈BrIN₃ (M+H)⁺: m/z=566.0; found566.0.

Step 3.6-Bromo-3-(1-methyl-1H-pyrazol-4-yl)-1-trityl-1H-pyrazolo[4,3-b]pyridine

6-Bromo-3-iodo-1-trityl-1H-pyrazolo[4,3-b]pyridine (5.0 g, 8.83 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(1.837 g, 8.83 mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (0.7 g, 0.883 mmol) andpotassium phosphate (2.81 g, 13.25 mmol) were placed in a round bottomflask and it was evacuated and backfilled with N₂ three times. Then1,4-dioxane (100 ml) and water (10 ml) were added and the reaction wasstirred at 70° C. for 1 h. Water was then added and the product wasextracted with EtOAc. The solution was washed with brine, dried andconcentrated. The residue was purified by Biotage Isolera to afford thedesired product. LC-MS calculated for C₂₉H₂₃BrN₅ (M+H)⁺: m/z=520.2;found: 520.2.

Step 4.N-Methyl-3-(1-methyl-1H-pyrazol-4-yl)-1-trityl-1H-pyrazolo[4,3-b]pyridin-6-amine

A microwave vial containing6-bromo-3-(1-methyl-1H-pyrazol-4-yl)-1-trityl-1H-pyrazolo[4,3-b]pyridine(0.460 g, 0.884 mmol),chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II)(0.069 g, 0.088 mmol) and cesium carbonate (0.576 g, 1.768 mmol) wassealed and evacuated and backfilled with nitrogen three times.1,4-Dioxane (12 ml) and a solution of methanamine (1.105 ml, 2.210 mmol)were added. The reaction mixture was heated to 100° C. for 2 h. Thenwater was added and the product was extracted with EtOAc. The combinedorganic phases were washed with brine, dried and concentrated. Theresidue was purified by Biotage Isolera to afford the desired product.LC-MS calculated for C₃₀H₂₇N₆ (M+H)⁺: m/z=471.2; found 471.2.

Step 5.5-Bromo-N-methyl-3-(1-methyl-1H-pyrazol-4-yl)-1-trityl-1H-pyrazolo[4,3-b]pyridin-6-amine

To a solution ofN-methyl-3-(1-methyl-1H-pyrazol-4-yl)-1-trityl-1H-pyrazolo[4,3-b]pyridin-6-amine(300 mg, 0.638 mmol) in DMF (5 ml) was added NBS (125 mg, 0.701 mmol).The reaction mixture was stirred at r.t for 2 h and then treated withwater. The product was extracted with DCM. The organic phase was washedwith water and brine, dried over Na₂SO₄, and concentrated. The residuewas purified by Biotage Isolera to afford the desired product. LC-MScalculated for C₃₀H₂₆BrN₆ (M+H)⁺: m/z=549.2; found 549.2.

Step 6.5-(2,3-Dimethylphenyl)-N-methyl-3-(1-methyl-1H-pyrazol-4-yl)-1-trityl-1H-pyrazolo[4,3-b]pyridin-6-amine

5-Bromo-N-methyl-3-(1-methyl-1H-pyrazol-4-yl)-1-trityl-1H-pyrazolo[4,3-b]pyridin-6-amine(100 mg, 0.182 mmol), (2,3-dimethylphenyl)boronic acid (0.030 g, 0.200mmol), Cs₂CO₃ (0.089 g, 0.273 mmol), Xphos PdG2 (3.46 mg, 9.10 μmol),were placed in a vial and the vial was evacuated and backfilled withnitrogen three times. 1,4-Dioxane (5 ml) and water (1.25 ml) were addedand the reaction mixture was stirred at 70° C. for 1 hr. The reactionmixture was quenched with water and the product was extracted with ethylacetate. The organic phase was washed with water and brine, dried oversodium sulfate and concentrated. The residue was purified by BiotageIsolera to afford the desired product. LC-MS calculated for C₃₈H₃₅N₆(M+H)⁺: m/z=575.2; found: 575.2.

Step 7.5-(2,3-Dimethylphenyl)-N-methyl-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-6-amine

5-(2,3-Dimethylphenyl)-N-methyl-3-(1-methyl-1H-pyrazol-4-yl)-1-trityl-1H-pyrazolo[4,3-b]pyridin-6-amine(0.060 g, 0.100 mmol) was dissolved in 2 ml of methylene chloride and 2ml of TFA was added. The reaction mixture was stirred at r.t for 1 hr.Most of the solvent was removed in vacuo and the residue was treatedwith water. The product was extracted with ethyl acetate, andneutralized to pH-7 with saturated NaHCO₃ solution. The organic phasewas separated, washed with water and brine, dried over sodium sulfateand concentrated. The residue was purified by prep-LCMS (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%TFA, at flow rate of 60 mL/min). The product was isolated as the TFAsalt. LC-MS calculated for C₁₉H₂₁N₆ (M+H)⁺: m/z=333.2; found: 333.2. ¹HNMR (500 MHz, DMSO-d6) δ 8.25-8.19 (s, 1H), 7.98-7.94 (s, 1H), 7.31-7.26(d, J=7.4 Hz, 1H), 7.25-7.20 (t, J=7.5 Hz, 1H), 7.12-7.05 (d, J=6.1 Hz,1H), 6.80-6.73 (s, 1H), 3.91-3.86 (s, 3H), 2.75-2.68 (s, 3H), 2.36-2.31(s, 3H), 1.99-1.88 (s, 3H) ppm.

Example 35.6-(Difluoromethyl)-5-(2,3-dihydro-1H-inden-4-yl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine

Step 1. 6-Bromo-5-chloro-2-methylpyridin-3-amine

NBS (6.51 g, 36.6 mmol) was added to a solution of5-chloro-2-methylpyridin-3-amine (4.97 g, 34.9 mmol) in DMF (349 ml).After stirring at r.t. for 30 min, water was added and precipitatedproduct was collected by filtration and dried overnight in the air. Thecrude product was used in the next step without further purification.LCMS calculated for C₆H₇N₂BrCl (M+H)⁺: m/z=221.0; found 221.0.

Step 2. N-(6-Bromo-5-chloro-2-methylpyridin-3-yl)acetamide

To a solution of 6-bromo-5-chloro-2-methylpyridin-3-amine (7.0 g, 31.6mmol) in acetic acid (79 mL) was added acetic anhydride (3.73 ml, 39.5mmol). The reaction was stirred at 50° C. for 1 h, water was then addedand the precipitated product was collected by filtration. It was used inthe next step without further purification. LCMS calculated forC₈H₉N₂BrClO (M+H)⁺: m/z=263.0; found 263.0.

Step 3. 1-(5-Bromo-6-chloro-1H-pyrazolo[4,3-b]pyridin-1-yl)ethan-1-one

To a suspension of N-(6-bromo-5-chloro-2-methylpyridin-3-yl)acetamide(7.2 g, 27.3 mmol) in toluene (137 ml) were added acetic anhydride (7.73ml, 82 mmol), potassium acetate (3.22 g, 32.8 mmol) and isopentylnitrite (5.87 ml, 43.7 mmol). The reaction mixture was heated at 100° C.for 2 h before dilution with EtOAc. The mixture was washed with sat.NaHCO₃ and brine, dried over Na₂SO₄. The solvent was removed undervacuum to afford the brown solid as the crude product which was useddirectly in next step without purification. LCMS calculated forC₈H₆N₃BrClO (M+H)⁺: m/z=274.0; found 274.0.

Step 4. 5-Bromo-6-chloro-1H-pyrazolo[4,3-b]pyridine

To a solution of1-(5-bromo-6-chloro-1H-pyrazolo[4,3-b]pyridin-1-yl)ethan-1-one (7 g,25.5 mmol) in THF (31.9 ml) and methanol (31.9 ml) was added 1M solutionof sodium hydroxide (38.3 ml, 38.3 mmol). The mixture was stirred at 50°C. for 1 h. After completion, most of solvent was evaporated before 1NHCl (40 mL) was added, followed by 200 mL of water. Brown solid slowlyformed during stirring of the reaction. The crude product was collectedby filtration and used in the next step without further purification.LCMS calculated for C₆H₄N₃BrCl (M+H)⁺: m/z=232.0; found 232.0.

Step 5. 5-Bromo-6-chloro-3-iodo-1H-pyrazolo[4,3-b]pyridine

To a solution of 5-bromo-6-chloro-1H-pyrazolo[4,3-b]pyridine (4.0 g,17.2 mmol) in 30 ml of DMF was added 1-iodopyrrolidine-2,5-dione (4.3 g,19.0 mmol), and the reaction mixture was stirred at r.t for 2 h. Themixture was poured into water (200 mL) and stirred for another 10 min.The resulting solid was filtered and air-dried. The resultant materialwas used in the next step without further purification. LC-MS calculatedfor C₆H₃BrClIN₃ (M+H)⁺: m/z=358.0; found 358.0.

Step 6.5-Bromo-6-chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine

To a suspension of 5-bromo-6-chloro-3-iodo-1H-pyrazolo[4,3-b]pyridine(5.0 g, 14.0 mmol) in DMF (40 ml) at 0° C. was added 60% NaH (0.72 g,18.0 mmol). After the addition was complete, the reaction was warmed tor.t and stirred at r.t. for 30 min. The mixture was cooled back to 0° C.when a solution of (2-(chloromethoxy)ethyl)trimethylsilane (3.0 g, 18.0mmol) in 10 mL of DMF was added. The reaction was stirred at r.t for 2h. Water was added to the reaction mixture and the product was extractedwith DCM. The organic phase was separated, dried over sodium sulfate andthe solvents were evaporated in vacuo. The residue was purified byBiotage Isolera to afford the desired product. LC-MS calculated forC₁₂H₁₇BrClIN₃OSi(M+H)⁺: m/z=488.2; found: 488.2.

Step 7.5-Bromo-6-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine

5-Bromo-6-chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine(1.50 g, 3.07 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.652 g, 3.13 mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (0.251 g, 0.307 mmol)and potassium phosphate (912 mg, 4.30 mmol) were placed in a vial andthe vial was evacuated and backfilled with N₂ three times. 1,4-Dioxane(10 ml) and water (2.0 ml) were added and the reaction was stirred at65° C. for 1 h. Then water was added and the product was extracted withEtOAc. The solution was washed with brine, dried and concentrated. Theresidue was purified by Biotage Isolera to afford the desired product.LC-MS calculated for C₁₆H₂₂BrCl₅OSi (M+H)⁺: m/z=442.2; found: 442.2.

Step 8.6-Chloro-5-(2,3-dihydro-1H-inden-4-yl)-3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine

5-Bromo-6-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine(700 mg, 1.58 mmol),2-(2,3-dihydro-1H-inden-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(463 mg, 1.9 mmol), ^(t)BuXPhos Pd G3 (175 mg, 0.22 mmol) and potassiumphosphate (0.356 ml, 4.30 mmol) were placed in a vial and the vial wasevacuated and backfilled with N₂ three times. 1,4-Dioxane (10 ml) andwater (2.0 ml) were added and reaction was stirred at 80° C. for 1 h.Then water was added and the product was extracted with EtOAc. Theorganic phase was washed with brine, dried and concentrated. The residuewas purified by Biotage Isolera to afford the desired product. LC-MScalculated for C₂₅H₃₁ClN₅OSi (M+H)⁺: m/z=480.2; found: 480.2.

Step 9.5-(2,3-Dihydro-1H-inden-4-yl)-3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-6-vinyl-1H-pyrazolo[4,3-b]pyridine

6-Chloro-5-(2,3-dihydro-1H-inden-4-yl)-3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine(200 mg, 0.42 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (83mg, 0.542 mmol), Cs₂CO₃ (271 mg, 0.833 mmol) and Xphos Pd G2 (31.7 mg,0.083 mmol) were placed in a vial and the vial was evacuated andbackfilled with N₂ three times. 1,4-Dioxane (5 ml) and water (1 ml) wereadded and the reaction was stirred at 75° C. for 1 h. Then water wasadded and the product was extracted with EtOAc. The organic phase waswashed with brine, dried over sodium sulfate and concentrated. Theresidue was purified by Biotage Isolera to afford the desired product.LC-MS calculated for C₂₇H₃₄N₅OSi (M+H)⁺: m/z=472.2; found: 472.2.

Step 10.5-(2,3-Dihydro-1H-inden-4-yl)-3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine-6-carbaldehyde

To a mixture of5-(2,3-dihydro-1H-inden-4-yl)-3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-6-vinyl-1H-pyrazolo[4,3-b]pyridine(0.250 g, 0.530 mmol) and sodium periodate (0.57 g, 2.65 mmol) intetrahydrofuran (5 ml) and water (1.5 ml), was added osmium (VIII)oxide, 4% in water (0.337 g, 0.053 mmol). The reaction mixture wasstirred at r.t. for 1 hour. It was quenched with saturated sodiumthiosulfate solution. The product was extracted with DCM (×3). Thecombined extracts were washed with water, brine, dried over sodiumsulfate and concentrated. The crude material was used to the next stepwithout further purification. LC-MS calculated for C₂₆H₃₂N₅O₂Si (M+H)⁺:m/z=474.2; found: 474.2.

Step 11.6-(Difluoromethyl)-5-(2,3-dihydro-1H-inden-4-yl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine

To a solution of5-(2,3-dihydro-1H-inden-4-yl)-3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine-6-carbaldehyde(20 mg, 0.042 mmol) in methylene chloride (2 mL) was added bydiethylaminosulfur trifluoride (11.22 μl, 0.084 mmol). After stirring atr.t. overnight, NaHCO₃ solution was added and the product was extractedwith DCM, organic phase was washed with brine, dried over Na₂SO₄ andconcentrated. The resultant residue was redissolved in 50% of TFA inCH₂Cl₂. After stirring at r.t. for 30 min, the solvents were evaporatedand aqueous ammonia was added. After stirring at r.t. for additional 30min, the reaction was diluted with CH₃CN and water and purified withprep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). Theproduct was isolated as the TFA salt. LC-MS calculated for C₂₀H₁₈F₂N₅(M+H)⁺: m/z=366.2; found: 366.2.

Example 36.(5-(2,3-Dihydro-1H-inden-4-yl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-6-yl)methanol

To a solution of5-(2,3-dihydro-1H-inden-4-yl)-3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine-6-carbaldehyde(Example 35, step 10) (20 mg, 0.042 mmol) in THF (2.0 ml) and MeOH (1.0ml) was added sodium borohydride (8 mg, 0.21 mmol) at 0° C. Afterstirring at r.t for 1 h, NaHCO₃ solution was added and the product wasextracted with EtOAc. The organic phase was washed with brine, driedover Na₂SO₄ and concentrated in vacuo. The resultant residue wasdissolved in 50% of TFA in CH₂Cl₂. After stirring at r.t. for 30 min,the solvents were evaporated and aqueous ammonia was added. Afterstirring at r.t. for additional 30 min, the reaction was diluted withCH₃CN and water and purified with prep-LCMS (XBridge C18 column, elutingwith a gradient of acetonitrile/water containing 0.1% TFA, at flow rateof 60 mL/min). The product was isolated as the TFA salt. LC-MScalculated for C₂₀H₂₀N₅O (M+H)⁺: m/z=346.2; found: 346.2.

Example 37.5-(2,3-Dihydro-1H-inden-4-yl)-N-methyl-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-6-amine

This compound was prepared according to the procedure described inExample 34, using2-(2,3-dihydro-1H-inden-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneinstead of (2,3-dimethylphenyl)boronic acid. The product was isolated asthe TFA salt. LC-MS calculated for C₂₀H₂₁N₆ (M+H)⁺: m/z=345.2; found345.2.

Example 38.(5-(2,3-Dimethylphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-6-yl)methanol

This compound was prepared according to the procedure described inExamples 35 and 36, using (2,3-dimethylphenyl)boronic acid instead of2-(2,3-dihydro-1H-inden-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.The product was isolated as the TFA salt. LC-MS calculated for C₁₉H₂₀N₅O(M+H)⁺: m/z=334.2; found 334.2. ¹H NMR (500 MHz, DMSO-d6) δ 8.34-8.26(s, 1H), 8.08-8.05 (s, 1H), 8.05-8.01 (s, 1H), 7.29-7.23 (d, J=7.4 Hz,1H), 7.23-7.16 (t, J=7.5 Hz, 1H), 7.08-7.00 (d, J=6.1 Hz, 1H), 4.36-4.17(m, 2H), 3.95-3.87 (s, 3H), 2.38-2.28 (s, 3H), 1.92-1.81 (s, 3H) ppm.

Example 39.4-(6-Chloro-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-2-ol

Step 1. 6-Bromo-5-chloro-2-methylpyridin-3-amine

NBS (10.4 g, 58.4 mmol) was added to a solution of5-chloro-2-methylpyridin-3-amine (7.9 g, 55.6 mmol) in DMF (100 ml).After stirring at r.t. for 10 min, water was added and the precipitatedproduct was collected by filtration. The resultant product was washedwith water and air dried. It was used in the next step without furtherpurification. LC-MS calculated for C₆H₇BrCl₂ (M+H)⁺: m/z=221.0 and223.0; found 221.0 and 223.0.

Step 2. N-(6-Bromo-5-chloro-2-methylpyridin-3-yl)acetamide

Acetic anhydride (6.3 ml, 66.3 mmol) was added to a solution of6-bromo-5-chloro-2-methylpyridin-3-amine (11.75 g, 53.1 mmol) in aceticacid (130 ml). After stirring at 50° C. for 1 h, water was added and theprecipitated product was collected by filtration. The resultant productwas washed with water and air dried. It was used in the next stepwithout further purification. LC-MS calculated for C₈H₉BrClN₂O (M+H)⁺:m/z=263.0 and 265.0; found 263.0 and 265.0.

Step 3. 1-(5-Bromo-6-chloro-1H-pyrazolo[4,3-b]pyridin-1-yl)ethan-1-one

To a suspension of N-(6-bromo-5-chloro-2-methylpyridin-3-yl)acetamide(12.7 g, 48.2 mmol) in toluene (120 ml) were added acetic anhydride(13.6 ml, 145 mmol), potassium acetate (5.7 g, 57.8 mmol) and isopentylnitrite (10.4 ml, 77 mmol). After heating at 110° C. for 2 h, thereaction mixture was cooled down to r.t. and EtOAc was added. Thenorganic phase was washed with NaHCO₃ solution, dried over sodiumsulfate, filtered, and the solvent was removed in vacuo. The resultantcrude product was purified by Biotage Isolera to give the desiredcompound.

Step 4. 5-Bromo-6-chloro-1H-pyrazolo[4,3-b]pyridine

Potassium carbonate (7.40 g, 53.6 mmol) was added to a solution of1-(5-bromo-6-chloro-1H-pyrazolo[4,3-b]pyridin-1-yl)ethan-1-one (13.37 g,48.7 mmol) in methanol (100 ml). After stirring at 60° C. for 1 h, waterwas added and the precipitated product was collected by filtration. Theresultant product was washed with water and air dried. It was used inthe next step without further purification. LC-MS calculated forC₆H₄BrClN₃ (M+H)⁺: m/z=232.0 and 234.0; found 232.0 and 234.0.

Step 5. tert-Butyl5-bromo-6-chloro-3-iodo-1H-pyrazolo[4,3-b]pyridine-1-carboxylate

NIS (4.95 g, 22 mmol) was added to a solution of5-bromo-6-chloro-1H-pyrazolo[4,3-b]pyridine (5 g, 21.55 mmol) in DMF (50ml). After stirring at 60° C. for 2 h, the reaction mixture was cooleddown to r.t., and triethylamine (6.26 ml, 44.9 mmol) and Boc-anhydride(8.17 g, 37.4 mmol) were added. After additional stirring at r.t. for 1h, water was added and the precipitated solid was collected byfiltration and air dried. The resultant product was used in the nextstep without further purification. LC-MS calculated for C₁₁H₁₁BrClIN₃O₂(M+H)⁺: m/z=457.9 and 459.9; found 457.9 and 459.9.

Step 6. tert-Butyl5-bromo-6-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine-1-carboxylate

tert-Butyl5-bromo-6-chloro-3-iodo-1H-pyrazolo[4,3-b]pyridine-1-carboxylate (5.36g, 11.69 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(2.48 g, 11.92 mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (0.96 g, 1.17 mmol) andpotassium phosphate (3.47 g, 16.37 mmol) were placed in a flask and theflask was evacuated and backfilled with N₂ three times. Then 1,4-dioxane(100 ml) and water (10 ml) were added and the reaction was stirred at80° C. for 1 h. After cooling to r.t., water was added and the desiredproduct was extracted with EtOAc. The organic phase was washed withbrine, dried over sodium sulfate and the solvent was removed in vacuo.Crude material was purified by Biotage Isolera. LC-MS calculated forC₁₅H₁₆BrClN₅O₂ (M+H)⁺: m/z=412.0 and 414.0; found 412.0 and 414.0.

Step 7.4-(6-Chloro-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-2-ol

tert-Butyl5-bromo-6-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine-1-carboxylate(265 mg, 0.642 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-ol(175 mg, 0.674 mmol),chloro[tri-tert-butylphosphine)-2-(2-aminobiphenyl)] palladium(II) (33.0mg, 0.064 mmol) and potassium phosphate (204 mg, 0.963 mmol) were placedin a vial and the vial was evacuated and backfilled with N₂ three times.After 1,4-dioxane (4 ml) and water (400 μl) were added, the reactionmixture was stirred at 80° C. for 1 h. The mixture was cooled to roomtemperature, diluted with DCM and filtered. The filtrate wasconcentrated in vacuo and the resultant residue was purified by BiotageIsolera. The resultant purified material was dissolved in 1,4-dioxane (6ml) and water (6 ml). After the addition of cesium carbonate (313 mg, 0.96 mmol) and morpholine (1 ml), the reaction mixture was heated at 100°C. for 2 h. The mixture was cooled to room temperature, diluted withDCM, washed with brine, dried over sodium sulfate, and the solvents wereremoved in vacuo. The two enantiomers of the product were separated withchiral SFC-PR-2 (Phenomenex LUX i-Cellulose-5 Sum 21.2×250 mm, elutingwith 30% of IPA in CO₂, at flow rate of 60 mL/min, t_(R, peak 1)=8.2min, t_(R, peak 2)=9.9 min). After the solvent was evaporated in vacuo,peak 2 was purified by prep-LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min). The product was isolated as the TFA salt. LC-MS calculated forC₁₉H₁₇ClN₅O (M+H)⁺: m/z=366.1; found 366.1.

Example 40.5-(2,3-Dimethylphenyl)-6-methyl-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine

To a vial were added tert-butyl6-chloro-5-(2,3-dimethylphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine-1-carboxylate(20 mg, 0.046 mmol, prepared in a similar way to Example 35, step 1-8),2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (11 mg, 0.09 mmol), Cs₂CO₃(30 mg, 0.091 mmol), XPhos PdG2 (4 mg, 0.009 mmol). The vial was sealedthen evacuated and backfilled with N₂ three times. After toluene (1.0ml) and water (0.2 ml) were added, the reaction mixture was heated at75° C. for 1 h. Then water was added and the product was extracted withEtOAc. The organic phase was washed with brine, dried over sodiumsulfate and concentrated. The resultant residue was dissolved in 50% ofTFA in CH₂Cl₂. After stirring at r.t. for 30 min, the reaction wasdiluted with CH₃CN and water and purified with prep-LCMS (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%TFA, at flow rate of 60 mL/min). The product was isolated as the TFAsalt. LC-MS calculated for C₁₉H₂₀N₅ (M+H)⁺: m/z=318.2; found: 318.2.

Example 41.5-(2,3-Dimethylphenyl)-6-methoxy-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine

A solution of tert-butyl5-(2,3-dimethylphenyl)-3-iodo-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate(Example 66, 25 mg, 0.052 mmol),1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine(47.4 mg, 0.156 mmol), Xphos Pd G2 (4.10 mg, 5.22 μmol), potassiumphosphate (44.3 mg, 0.209 mmol) in water (0.100 ml) and dioxane (1 ml)was heated to 80° C. for 20 hrs. After this time it was cooled to r.t.,diluted with water and extracted with EtOAc. The combined organic phaseswere washed with sat. aq. NaCl and dried over Na₂SO₄, then filtered andconcentrated to dryness. The residue was then dissolved in DCM (1 mL)and TFA (1 mL) was added. The mixture was stirred at r.t. for 1 h andpurified by prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). Theproduct was isolated as the TFA salt. LCMS calculated for C₂₅H₂₉N₆O(M+H)⁺: m/z=429.2; found 429.0. ¹H NMR (500 MHz, DMSO-d6) δ 10.02 (s,1H), 9.21 (d, J=2.3 Hz, 1H), 8.50 (dd, J=9.0, 2.3 Hz, 1H), 7.52 (s, 1H),7.23 (d, J=7.1 Hz, 1H), 7.17 (t, J=7.5 Hz, 1H), 7.13-7.05 (m, 2H), 4.46(d, J=13.2 Hz, 2H), 3.84 (s, 3H), 3.57-3.46 (m, 2H), 3.25-3.02 (m, 4H),2.85 (s, 3H), 2.32 (s, 3H), 1.98 (s, 3H) ppm.

Alternative Synthesis of5-(2,3-Dimethylphenyl)-6-methoxy-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridineStep 1. 6-Bromo-1-trityl-1H-pyrazolo[4,3-b]pyridine

NaH (60% in mineral oil, 2.46 g, 61.6 mmol) was slowly added at 0° C. toa solution of 6-bromo-1H-pyrazolo[4,3-b]pyridine (10.16 g, 51.3 mmol) inDMF (70 ml). After stirring at r.t. for 20 min,(chloromethanetriyl)tribenzene (15.73 g, 56.4 mmol) was slowly added andthe reaction mixture was stirred at r.t. for 1 h. Then water was addedand the precipitated product was collected by filtration, washed withwater and air dried. It was used in the next step without furtherpurification. LC-MS calculated for C₂₅H₁₉BrN₃ (M+H)⁺: m/z=440.1 and442.1; found 440.0 and 442.0.

Step 2. 6-Methoxy-1-trityl-1H-pyrazolo[4,3-b]pyridine

A mixture of 6-bromo-1-trityl-1H-pyrazolo[4,3-b]pyridine (25.0 g, 56.8mmol), cesium carbonate (25.9 g, 79 mmol), methanol (6.89 ml, 170 mmol)and ^(t)BuXPhosPd G3 (1.52 g, 1.7 mmol) in toluene (150 ml) was heatedat 80° C. for 1 h. After cooling to r.t., the reaction mixture wasfiltered, the solvent evaporated in vacuo and the crude material waspurified by Biotage Isolera. LCMS calculated for C₂₆H₂₂N₃O (M+H)⁺:m/z=392.2; Found: 392.1.

Step 3. 6-Methoxy-1-trityl-1H-pyrazolo[4,3-b]pyridine 4-oxide

m-CPBA (14.5 g, 64.6 mmol) was slowly added at 0° C. to a solution of6-methoxy-1-trityl-1H-pyrazolo[4,3-b]pyridine (16.8 g, 43.0 mmol) in DCM(150 ml). After stirring at r.t. overnight, the reaction was treatedwith Na₂S₂O₃ solution and 1M NaOH solution. After stirring at r.t. for30 min, the organic phase was separated and washed 3 times with 1M NaOHsolution and 2 times with brine solution. Then the organic phase wasdried over sodium sulfate, filtered and the solvent was removed invacuo. The resultant product was used in the next step without furtherpurification. LC-MS calculated for C₂₆H₂₂N₃O₂ (M+H)⁺: m/z=408.2; found408.2.

Step 4. 5-Chloro-6-methoxy-1-trityl-1H-pyrazolo[4,3-b]pyridine

A solution of oxalyl chloride (5.36 ml, 61.3 mmol) in DCM was slowlyadded at 0° C. to a solution of6-methoxy-1-trityl-1H-pyrazolo[4,3-b]pyridine 4-oxide (16.65 g, 40.9mmol) and DIPEA (14.27 ml, 82 mmol) in DCM (100 ml). After stirring at0° C. for 1 h, the reaction was diluted with DCM and carefully treatedwith water. The organic phase was separated, washed 3 times with water,2 times with saturated NaHCO₃ solution, 2 times with brine and was driedover sodium sulfate. After removing the solvent in vacuo, the resultantproduct was used in the next step without further purification. LC-MScalculated for C₂₆H₂₁ClN₃O (M+H)⁺: m/z=426.1; found 426.2.

Step 5.5-(2,3-Dimethylphenyl)-6-methoxy-1-trityl-1H-pyrazolo[4,3-b]pyridine

A mixture of 5-chloro-6-methoxy-1-trityl-1H-pyrazolo[4,3-b]pyridine(11.29 g, 26.5 mmol), (2,3-dimethylphenyl)boronic acid (11.93 g, 80mmol), XphosPd G2 (4.17 g, 5.30 mmol), and potassium phosphate (22.51 g,106 mmol) in dioxane (100 ml) and water (10 ml) was heated to 85° C. for2 hrs. After this time the solution was cooled to r.t., diluted withwater and extracted with EtOAc. The combined organic phases were washedwith sat. aq. NaCl, dried over Na₂SO₄, filtered, and concentrated todryness. The obtained crude was used directly in the next step. LCMScalculated for C₃₄H₃₀N₃O (M+H)⁺: m/z=496.2; found 496.4.

Step 6. 5-(2,3-Dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine

To a solution of5-(2,3-dimethylphenyl)-6-methoxy-1-trityl-1H-pyrazolo[4,3-b]pyridine (13g, 26.2 mmol) in 100 mL CH₂Cl₂ was added TFA (40 ml) and water (2 ml)and the resulting solution was stirred at r.t. After 1.5 hrs, 250 mLsolution of MeCN:H₂O (1:1) was added. The mixture was stirred foradditional 10 min and the organic solvent was removed in vacuo. Theprecipitated solid was filtered off and the filtrate was washed 3 timeswith 200 mL EtOAc/hexanes (1:1). The aqueous phase was separated andconcentrated. The obtained crude was then taken up in 100 mL CH₂Cl₂ and100 mL H₂O. The mixture was neutralized with aq. NH₄OH. The organicphase was separated and washed 2 times with water. The obtained organicphase was then dried over Na₂SO₄, filtered and concentrated to obtainthe desired product. LCMS calculated for C₁₅H₁₆N₃O (M+H)⁺: m/z=254.1;found 254.2.

Step 7. tert-Butyl5-(2,3-dimethylphenyl)-3-iodo-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate

N-Iodosuccinimide (20.38 g, 91 mmol) was added to a solution of5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine (15.3 g,60.4 mmol) in DMF (100 ml). After stirring at 60° C. for 4 hrs, thereaction mixture was cooled to r.t., and N,N-diisopropylethylamine (31.6ml, 181 mmol) and di-tert-butyl dicarbonate (39.5 g, 181 mmol) wereadded. The resulting reaction mixture was then stirred at r.t. for 1.5hrs. The reaction mixture was then treated with water, extracted withEtOAc, washed with brine. The combined organic phases were washed 3times with water and concentrated. The crude was taken up in MeOH (ca.150 mL) and the precipitated solid was collected by filtration and driedto obtain the desired product. LCMS calculated for C₂₀H₂₃IN₃O₃ (M+H)⁺:m/z=480.1; found 480.2.

Step 8.5-(2,3-Dimethylphenyl)-6-methoxy-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine

A solution of tert-butyl5-(2,3-dimethylphenyl)-3-iodo-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate(25 mg, 0.052 mmol),1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine(47.4 mg, 0.156 mmol), XphosPd G2 (4.10 mg, 5.22 μmol), potassiumphosphate (44.3 mg, 0.209 mmol) in water (0.1 ml) and dioxane (1 ml) washeated to 80° C. for 20 hrs. After this time it was cooled to r.t.,diluted with water and the product was extracted with EtOAc. Thecombined organic phases were washed with sat. aq. NaCl, dried overNa₂SO₄, filtered, and concentrated to dryness. The residue was thendissolved in DCM (1 mL) and TFA (1 mL) was added. The mixture wasstirred at r.t. for 1 h and purified by prep-LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min). The title compound was isolated as the TFAsalt. LCMS calculated for C₂₅H₂₉N₆O (M+H)⁺: m/z=429.2; found 429.0.

¹H NMR (500 MHz, DMSO-d6) δ 10.02 (s, 1H), 9.21 (d, J=2.3 Hz, 1H), 8.50(dd, J=9.0, 2.3 Hz, 1H), 7.52 (s, 1H), 7.23 (d, J=7.1 Hz, 1H), 7.17 (t,J=7.5 Hz, 1H), 7.13-7.05 (m, 2H), 4.46 (d, J=13.2 Hz, 2H), 3.84 (s, 3H),3.57-3.46 (m, 2H), 3.25-3.02 (m, 4H), 2.85 (s, 3H), 2.32 (s, 3H), 1.98(s, 3H) ppm.

Example 42.5-(2,3-Dimethylphenyl)-3-(6-(4-ethylpiperazin-1-yl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine

This compound was prepared according to the procedure described inExample 41, using1-ethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazineinstead of1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine.The product was isolated as the TFA salt. LC-MS calculated for C₂₆H₃₁N₆O(M+H)⁺: m/z=443.3; found 443.4.

Example 43.1-(4-(5-(5-(2,3-Dimethylphenyl)-6-methoxy-1H-pyrzolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperazin-1-yl)ethan-1-one

This compound was prepared according to the procedure described inExample 41, using1-(4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazin-1-yl)ethan-1-oneinstead of1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine.The product was isolated as the TFA salt. LC-MS calculated forC₂₆H₂₉N₆O₂ (M+H)⁺: m/z=457.2; found 457.1.

Example 44.4-(5-(5-(2,3-Dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)morpholine

This compound was prepared according to the procedure described inExample 41, using4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholineinstead of1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine.The product was isolated as the TFA salt. LC-MS calculated forC₂₄H₂₆N₅O₂ (M+H)⁺: m/z=416.2; found 416.1.

Example 45.4-(5-(5-(2,3-Dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-1-methylpiperazin-2-one

Step 1.5-(2,3-Dimethylphenyl)-3-(6-fluoropyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine

A solution of tert-butyl5-(2,3-dimethylphenyl)-3-iodo-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate(150 mg, 0.313 mmol), (6-fluoropyridin-3-yl)boronic acid (132 mg, 0.939mmol), Xphos Pd G2 (24.62 mg, 0.031 mmol) and potassium phosphate (266mg, 1.25 mmol) in dioxane (5 ml) and water (0.500 ml) was heated to 80°C. for 12 hrs. After this time it was cooled to r.t., diluted with waterand extracted with EtOAc. The combined organic phases were washed withsat. aq. NaCl, dried with Na₂SO₄, then filtered and concentrated todryness. The residue was then dissolved in DCM (2 mL) and TFA (2 mL) wasadded. The mixture was stirred at r.t. for 1 h and purified by silicagel chromatography to afford the desired product. LCMS calculated forC₂₀H₁₈FN₄O (M+H)⁺: m/z=349.1; found 349.1.

Step 2.4-(5-(5-(2,3-Dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-1-methylpiperazin-2-one

A solution of5-(2,3-dimethylphenyl)-3-(6-fluoropyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine(20 mg, 0.057 mmol), 1-methylpiperazin-2-one hydrochloride (25.9 mg,0.172 mmol), and N,N-diisopropylethylamine (100 μl, 0.574 mmol) in DMSO(0.5 ml) was heated to 120° C. for 20 hrs. The mixture was cooled tor.t. and purified by prep-LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min). The product was isolated as the TFA salt. LCMS calculated forC₂₅H₂₇N₆O₂ (M+H)⁺: m/z=443.2; found 443.2.

Example 46.1-(5-(5-(2,3-Dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidin-4-ol

This compound was prepared according to the procedure described inExample 45, using piperidin-4-ol instead of 1-methylpiperazin-2-onehydrochloride. The product was isolated as the TFA salt. LC-MScalculated for C₂₅H₂₈N₅O₂ (M+H)⁺: m/z=430.2; found 430.2.

Example 47.(R)-5-(2,3-Dimethylphenyl)-3-(6-(3,4-dimethylpiperazin-1-yl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine

This compound was prepared according to the procedure described inExample 45, using (R)-1,2-dimethylpiperazine dihydrochloride instead of1-methylpiperazin-2-one hydrochloride. The product was isolated as theTFA salt. LC-MS calculated for C₂₆H₃₁N₆O (M+H)⁺: m/z=443.3; found 443.4.

Example 48.5-(2,3-Dimethylphenyl)-6-(methoxy-d3)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine

Step 1. 6-(Methoxy-d3)-1-trityl-1H-pyrazolo[4,3-b]pyridine

A mixture of 6-bromo-1-trityl-1H-pyrazolo[4,3-b]pyridine (Example 1,step 1; 10.0 g, 22.7 mmol), cesium carbonate (11.10 g, 34.1 mmol),methanol-d₄ (6.89 ml) and ^(t)BuXPhos Pd G3 (0.18 g, 0.22 mmol) intoluene (70 ml) was heated at 80° C. for 1 h. After cooling to r.t. thereaction mixture was filtered, the solvent evaporated in vacuo and thecrude material was purified by Biotage Isolera. LCMS calculated forC₂₆H₁₉D₃N₃O (M+H)⁺: m/z=395.2; Found: 395.2.

Step 2. 6-(Methoxy-d3)-1-trityl-1H-pyrazolo[4,3-b]pyridine 4-oxide

3-Chlorobenzoperoxoic acid (9.33 g, 40.6 mmol) was slowly added at 0° C.to a solution of 6-(methoxy-d3)-1-trityl-1H-pyrazolo[4,3-b]pyridine (8g, 20.28 mmol) in DCM (100 mL). After stirring at r.t. overnight, thereaction was treated with Na₂S₂O₃ solution and 1M NaOH solution. Afterstirring at r.t. for 30 min, the organic phase was separated and washed3 times with 1M NaOH solution and 2 times with brine solution. Theorganic phase was dried over sodium sulfate, filtered and the solventwas removed in vacuo. The resultant product was used in the next stepwithout further purification. LC-MS calculated for C₂₆H₁₉D₃N₃O₂ (M+H)⁺:m/z=411.2; found 411.2.

Step 3. 5-Chloro-6-(methoxy-d3)-1-trityl-1H-pyrazolo[4,3-b]pyridine

A solution of oxalyl chloride (2.65 ml, 30.3 mmol) in DCM was slowlyadded at 0° C. to a solution of6-(methoxy-d3)-1-trityl-1H-pyrazolo[4,3-b]pyridine 4-oxide (8.3 g, 20.22mmol) and DIEA (10.59 mL, 60.7 mmol) in DCM (100 ml). After stirring at0° C. for 1 h, the reaction was diluted with DCM and carefully treatedwith water. The organic phase was separated, washed 3 times with water,2 times with saturated NaHCO₃ solution, 2 times with brine and driedover sodium sulfate. After removing the solvent in vacuo, the resultantproduct was used in the next step without further purification. LC-MScalculated for C₂₆H₁₈D3ClN₃O (M+H)⁺: m/z=429.1; found 429.2.

Step 4.5-(2,3-Dimethylphenyl)-6-(methoxy-d3)-1-trityl-1H-pyrazolo[4,3-b]pyridine

5-Chloro-6-(methoxy-d3)-1-trityl-1H-pyrazolo[4,3-b]pyridine (1.1 g, 2.56mmol), (2,3-dimethylphenyl)boronic acid (0.577 g, 3.85 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(0.205 g, 0.256 mmol) and K₃PO₄ (1.1 g, 5.13 mmol) were placed in aflask and the flask was evacuated and backfilled with N₂ three times.After 1,4-dioxane (10 mL) and water (1 mL) were added, the reactionmixture was stirred at 100° C. for 1 h. After cooling to r.t., water wasadded and the desired product was extracted with EtOAc. The organicphase was washed with brine, dried over sodium sulfate and the solventwas evaporated in vacuo. Crude material was purified by Biotage Isolera.LCMS calculated for C₃₄H₂₇D₃N₃O (M+H)⁺: m/z=499.3; Found: 499.2.

Step 5. 5-(2,3-Dimethylphenyl)-6-(methoxy-d3)-1H-pyrazolo[4,3-b]pyridine

TFA (10 mL) and water (1 mL) were added to a solution of5-(2,3-dimethylphenyl)-6-(methoxy-d3)-1-trityl-1H-pyrazolo[4,3-b]pyridine(1.0 g, 2.0 mmol) in DCM (10 mL). After stirring at r.t. for 30 min,CH₃CN and water were added and DCM was evaporated in vacuo. Theprecipitated solid was filtered off. The reaction mixture was furtherdiluted with water and was washed 3 times with EtOAc/hexane 1:1 mixture.The water phase was separated and all solvents were removed in vacuo.The residue was dissolved in DCM and neutralized with NaHCO₃ solution.The organic phase was further washed 2 times with NaHCO₃ solution,brine, then dried over sodium sulfate. The solvent was evaporated invacuo. The resultant crude product was used in the next step withoutfurther purification. LC-MS calculated for C₁₅H₁₃D₃N₃O (M+H)⁺:m/z=257.1; found 257.1.

Step 6.5-(2,3-Dimethylphenyl)-3-iodo-6-(methoxy-d3)-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine

1-Iodopyrrolidine-2,5-dione (614 mg, 2.73 mmol) was added to a solutionof 5-(2,3-dimethylphenyl)-6-(methoxy-d3)-1H-pyrazolo[4,3-b]pyridine (700mg, 2.73 mmol) in DMF (5 mL). After stirring at 80° C. for 1 h, thereaction mixture was cooled to r.t., and Cs₂CO₃ (1.7 g, 5.46 mmol) and1-(chloromethyl)-4-methoxybenzene (535 μl, 4.10 mmol) were added. Afteradditional stirring at 80° C. for 1 h, water was added and the desiredproduct was extracted with EtOAc. The organic phase was washed withbrine, dried over sodium sulfate and the solvent was evaporated invacuo. Crude material was purified by Biotage Isolera. LCMS calculatedfor C₂₃H₂₀D₃IN₃O₂ (M+H)⁺: m/z=503.1; Found: 503.1.

Step 7.5-(2,3-Dimethylphenyl)-6-(methoxy-d3)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine

A solution of5-(2,3-dimethylphenyl)-3-iodo-6-(methoxy-d3)-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine(25 mg, 0.050 mmol),1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine(47.4 mg, 0.156 mmol), Xphos Pd G2 (4.10 mg, 5.22 μmol), potassiumphosphate (44.3 mg, 0.209 mmol) in water (0.100 mL) and 1,4-dioxane (1mL) was heated to 80° C. for 2 h. The reaction mixture was then cooledto r.t., diluted with water and extracted with EtOAc. The combinedorganic phases were washed with sat. aq. NaCl, dried over Na₂SO₄,filtered, and concentrated to dryness. The residue was then dissolved intriflic acid (0.5 mL). The mixture was stirred at r.t. for 1 h, dilutedwith CH₃CN and purified by prep-LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min). The product was isolated as the TFA salt. LCMS calculated forC₂₅H₂₆D₃N₆O (M+H)+: m/z=432.2; found 432.3.

Example 49.5-(2,3-Dimethylphenyl)-6-methoxy-3-(6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine

This compound was prepared according to the procedure described inExample 45, using (1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptanedihydrobromide instead of 1-methylpiperazin-2-one hydrochloride. Theproduct was isolated as the TFA salt. LC-MS calculated for C₂₆H₂₉N₆O(M+H)⁺: m/z=441.2; found 441.3.

Example 50.1-(5-(5-(2,3-Dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-N,N-dimethylpiperidine-4-carboxamide

This compound was prepared according to the procedure described inExample 45, using N,N-dimethylpiperidine-4-carboxamide instead of1-methylpiperazin-2-one hydrochloride. The product was isolated as theTFA salt. LC-MS calculated for C₂₈H₃₃N₆O₂ (M+H)⁺: m/z=485.3; found485.3.

Example 51.1-(5-(5-(2,3-Dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-4-methylpiperidine-4-carboxylicacid

Step 1. tert-Butyl1-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-4-methylpiperidine-4-carboxylate

This compound was prepared according to the procedure described inExample 45, using tert-butyl 4-methylpiperidine-4-carboxylatehydrochloride instead of 1-methylpiperazin-2-one hydrochloride. LCMScalculated for C₃₁H₃₈N₅O₃(M+H)⁺: m/z=528.3; found 528.5.

Step 2.1-(5-(5-(2,3-Dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-4-methylpiperidine-4-carboxylicacid

This compound was prepared by treating tert-butyl1-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-4-methylpiperidine-4-carboxylatewith TFA in DCM, followed by purification by prep-LCMS (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%TFA, at flow rate of 60 mL/min). The product was isolated as the TFAsalt. LC-MS calculated for C₂₇H₃₀N₅O₃ (M+H)⁺: m/z=472.2; found 472.4.

Example 52.3-(4-(5-(2-Fluoro-3-methylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)-N,N-dimethylazetidine-1-carboxamide

Step 1.5-(2-Fluoro-3-methylphenyl)-6-methoxy-1-trityl-1H-pyrazolo[4,3-b]pyridine

5-chloro-6-methoxy-1-trityl-1H-pyrazolo[4,3-b]pyridine (Example 14, Step4; 0.50 g, 1.174 mmol), (2-fluoro-3-methylphenyl)boronic acid (0.217 g,1.41 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(0.094 g, 0.117 mmol) and potassium phosphate (0.498 g, 2.348 mmol) wereplaced in a flask and the flask was evacuated and backfilled with N₂three times. After 1,4-dioxane (5 ml) and water (500 μl) were added, thereaction mixture was stirred at 100° C. for 1 h. After this time it wascooled to r.t., diluted with water and extracted with EtOAc three times.The combined organic phases were washed with sat. NaCl, dried withNa₂SO₄, filtered and concentrated to dryness. The residue was purifiedby silica gel chromatography to afford the desired product. LC-MScalculated for C₃₃H₂₇FN₃O (M+H)⁺: m/z=500.2; found 500.2.

Step 2. 5-(2-Fluoro-3-methylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine

TFA (1.2 ml, 16 mmol) and water (0.03 ml, 1.6 mmol) were added to asolution of5-(2-fluoro-3-methylphenyl)-6-methoxy-1-trityl-1H-pyrazolo[4,3-b]pyridine(400 mg, 0.80 mmol) in DCM (2 mL). After stirring at r.t. for 30 min,CH₃CN and water were added and DCM was evaporated in vacuo. Precipitatedsolid was filtered off. The reaction mixture was further diluted withwater and was washed 3 times with EtOAc/hexane 1:1 mixture. The waterphase was separated and all solvents were removed in vacuo. The residuewas dissolved in DCM and neutralized with NaHCO₃ solution. The organicphase was further washed 2 times with NaHCO₃ solution, brine, then driedand the solvent evaporated in vacuo. The resultant crude product wasused in the next step without further purification. LC-MS calculated forC₁₄H₁₃FN₃O (M+H)⁺: m/z=258.1; found 258.2.

Step 3.5-(2-Fluoro-3-methylphenyl)-3-iodo-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine

To a solution of5-(2-fluoro-3-methylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine (200mg, 0.777 mmol) in DMF (2 mL) was added 1-iodopyrrolidine-2,5-dione (192mg, 0.855 mmol). The reaction was warmed up to 80° C. and stirred atthat temperature for 1 h. After this time the reaction mixture wascooled to r.t, and 1-(chloromethyl)-4-methoxybenzene (146 mg, 0.933mmol) and Cs₂CO₃ (380 mg, 1.166 mmol) were added. The reaction mixturewas stirred at 90° C. for 1 h. After this time it was cooled to r.t.,diluted with water and extracted with EtOAc three times. The combinedorganic phases were washed with sat. NaCl, dried over Na₂SO₄, filteredand concentrated to dryness. The residue was purified by Biotage Isolerato afford the desired product. LC-MS calculated for C₂₂H₂₀IFN₃O₂ (M+H)⁺:m/z=504.1; found 504.0.

Step 4. tert-Butyl3-(4-(5-(2-fluoro-3-methylphenyl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate

To a solution of5-(2-fluoro-3-methylphenyl)-3-iodo-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine(320 mg, 0.636 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) was addedtert-butyl3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate(266 mg, 0.763 mmol), potassium phosphate (270 mg, 1.272 mmol), and[dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (51.9 mg, 0.064 mmol. The reaction was degassedwith N₂ and stirred at 80° C. for 2 h. After this time it was cooled tor.t., diluted with EtOAc, washed sequentially with water, sat. NaCl anddried over Na₂SO₄. The organic phases were filtered and concentrated todryness. The residue was purified by Biotage Isolera to afford thedesired product. LC-MS calculated for C₃₃H₃₆FN₆O₄ (M+H)⁺: m/z=599.3;found 599.3.

Step 5.3-(4-(5-(2-Fluoro-3-methylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)-N,N-dimethylazetidine-1-carboxamide

To a solution of tert-butyl3-(4-(5-(2-fluoro-3-methylphenyl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate(20 mg, 0.033 mmol) in DCM (1 ml) was added 0.5 ml of TFA. The reactionwas stirred for 1 h before concentration to dryness. The crude materialwas dissolved in DCM (1 ml), to which was then added TEA (9.31 μl, 0.067mmol) and dimethylcarbamic chloride (3.95 mg, 0.037 mmol). The reactionmixture was stirred at r.t. for 1 h, followed by adding 0.5 ml oftriflic acid. After additional stirring at r.t. for 2 h, the reactionwas diluted with water and MeOH, then purified by prep-LCMS (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%TFA, at flow rate of 60 mL/min). The product was isolated as the TFAsalt. LCMS calculated for C₂₃H₂₅FN₇O₂ (M+H)⁺: m/z=450.2; found 450.2.

Example 53.N-((cis)-4-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)cyclohexyl)acetamide

Step 1.5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1-trityl-1H-pyrazolo[4,3-b]pyridine

5-Chloro-6-methoxy-1-trityl-1H-pyrazolo[4,3-b]pyridine (Example 14, Step4; 0.50 g, 1.174 mmol),2-(2,3-dihydro-1H-inden-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(0.344 g, 1.409 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(0.094 g, 0.117 mmol) and potassium phosphate (0.498 g, 2.348 mmol) wereplaced in a vial and the vial was evacuated and backfilled with N₂ threetimes. After 1,4-dioxane (5 ml) and water (500 μl) were added, thereaction mixture was stirred at 100° C. for 1 h. After this time it wascooled to r.t., diluted with water and extracted with EtOAc three times.The combined organic phases were washed with sat. NaCl, dried withNa₂SO₄, filtered and concentrated to dryness. The residue was purifiedby Biotage Isolera to afford the desired product. LC-MS calculated forC₃₅H₃₀N₃O (M+H)⁺: m/z=508.2; found 508.2.

Step 2.5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine

TFA (1.23 ml, 16 mmol) and water (0.028 ml, 1.6 mmol) were added to asolution of5-(2-fluoro-3-methylphenyl)-6-methoxy-1-trityl-1H-pyrazolo[4,3-b]pyridine(400 mg, 0.80 mmol) in DCM (2 mL). After stirring at r.t. for 30 min,CH₃CN and water were added and DCM was evaporated in vacuo. Precipitatedsolid was filtered off. The reaction mixture was further diluted withwater and was washed 3 times with EtOAc/hexane 1:1 mixture. The waterphase was separated and all solvents were removed in vacuo. The residuewas dissolved in DCM and neutralized with NaHCO₃ solution. The organicphase was further washed 2 times with NaHCO₃ solution, brine, then driedand the solvent was evaporated in vacuo. The resultant crude product wasused in the next step without further purification. LC-MS calculated forC₁₆H₁₆N₃O (M+H)⁺: m/z=266.1; found 266.1.

Step 3.5-(2,3-Dihydro-1H-inden-4-yl)-3-iodo-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine

To a solution of5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine (190mg, 0.74 mmol) in DMF (2 mL) was added 1-iodopyrrolidine-2,5-dione (180mg, 0.81 mmol). The reaction was warmed up to 80° C. and stirred at thattemperature for 1 h. After this time the reaction mixture was cooled tor.t and 1-(chloromethyl)-4-methoxybenzene (131 mg, 0.90 mmol) and Cs₂CO₃(380 mg, 1.166 mmol) were added. The reaction mixture was stirred at 90°C. for 1 h. After this time it was cooled to r.t., diluted with waterand extracted with EtOAc three times. The combined organic phases werewashed with sat. NaCl, dried with Na₂SO₄, filtered and concentrated todryness. The residue was purified by Biotage Isolera to afford thedesired product. LC-MS calculated for C₂₄H₂₃IN₃O₂ (M+H)⁺: m/z=512.1;found 512.0.

Step 4.5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-3-0H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine

To a solution of5-(2,3-dihydro-1H-inden-4-yl)-3-iodo-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine(300 mg, 0.587 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) was addedtert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(207 mg, 0.704 mmol), potassium phosphate (249 mg, 1.173 mmol) and[dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (47.9 mg, 0.059 mmol). The reaction was degassedwith N₂ and stirred at 80° C. for 2 h. After this time it was cooled tor.t., and 2 mL of TFA was added. The reaction was stirred for additional30 min before dilution with EtOAc. The organic solution was washedsequentially with water, sat. NaCl and dried over Na₂SO₄. The organicphases were filtered and concentrated to dryness. The residue waspurified by Biotage Isolera to afford the desired product. LC-MScalculated for C₂₇H₂₆N₅O₂ (M+H)⁺: m/z=452.2; found 452.2.

Step 5.N-((cis)-4-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)cyclohexyl)acetamide

In a vial N-((trans)-4-hydroxycyclohexyl)acetamide (13.93 mg, 0.089mmol) and TEA (12.4 μl, 0.089 mmol) were dissolved in DCM (1 ml).Methanesulfonyl chloride (6.90 μl, 0.089 mmol) was added to the reactionmixture dropwise over 5 min at 0° C. After stirring at r.t. for 30 min,saturated NaHCO₃ solution was added to the reaction mixture followed byextraction with dichloromethane. The combined organic phases were driedover Na₂SO₄, filtered and concentrated. An acetonitrile (1 ml) solutionof5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-3-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine(20 mg, 0.044 mmol) and Cs₂CO₃ (28.9 mg, 0.089 mmol) were added to theresultant material. The reaction mixture was heated to 100° C. After 5h, triflic acid (0.5 ml) was added to the reaction mixture at r.t. After10 min, the reaction mixture was diluted with MeOH then purified byprep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). Theproduct was isolated as the TFA salt. LC-MS calculated for C₂₇H₃₁N₆O₂(M+H)+: m/z=471.2; found 471.2.

Example 54.5-(2,3-Dihydro-1H-inden-4-yl)-3-(6-(2,4-dimethylpiperazin-1-yl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine

Step 1.3-(6-Chloropyridin-3-yl)-5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine

To a solution of5-(2,3-dihydro-1H-inden-4-yl)-3-iodo-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine(Example 53, step 3; 500 mg, 0.98 mmol) in 1,4-dioxane (4 mL) and water(1 mL) was added (6-chloropyridin-3-yl)boronic acid (185 mg, 1.173mmol), potassium phosphate (415 mg, 1.956 mmol), and[dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (80 mg, 0.098 mmol). The reaction was degassedwith N₂ and stirred at 80° C. for 8 h. After this time it was cooled tor.t. before dilution with EtOAc. The resultant solution was washedsequentially with water, sat. NaCl and dried over Na₂SO₄. The organicphases were filtered and concentrated to dryness. The residue waspurified by silica gel chromatography to afford the desired product.LC-MS calculated for C₂₉H₂₆ClN₄O₂ (M+H)⁺: m/z=497.2; found 497.2.

Step 2.5-(2,3-Dihydro-1H-inden-4-yl)-3-(6-(2,4-dimethylpiperazin-1-yl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine

To a solution of3-(6-chloropyridin-3-yl)-5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine(20 mg, 0.040 mmol) in 1,4-dioxane (0.5 mL) was added1,3-dimethylpiperazine (4.6 mg, 0.04 mmol), sodium tert-butoxide (7.7mg, 0.080 mmol), andchloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(3.29 mg, 4.02 μmol). The reaction was degassed with N₂ and stirred at100° C. After 1 h, triflic acid (0.5 mL) was added to the reactionmixture at r.t. After 10 min, the reaction mixture was diluted withMeOH, then purified by prep-LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min). The product was isolated as the TFA salt. LC-MS calculated forC₂₇H₃₁N₆O (M+H)+: m/z=455.3; found 455.3.

Example 55.2-(3-(3-(6-(4-Acetylpiperazin-1-yl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2-methylphenyl)acetonitrile

Step 1. tert-Butyl5-(3-(cyanomethyl)-2-methylphenyl)-3-iodo-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate

This compound was prepared according to the procedures described inExample 14, using2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetonitrile(Intermediate 1) instead of2-(2,3-dihydro-1H-inden-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane asstarting material. LC-MS calculated for C₂₁H₂₂IN₄O₃ (M+H)⁺: m/z=505.1;found 505.0.

Step 2.2-(3-(3-(6-(4-acetylpiperazin-1-yl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2-methylphenyl)acetonitrile

To a solution of tert-butyl 5-(3-(cyanomethyl)-2-methylphenyl)-3-iodo-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate(20 mg, 0.040 mmol) in 1,4-dioxane (0.5 mL) and water (0.1 mL) was added1-(4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazin-1-yl)ethan-1-one (16 mg, 0.048 mmol), potassiumphosphate (16 mg, 0.079 mmol), and[dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (3 mg, 4 mop. The reaction was degassed with N₂and stirred at 80° C. for 2 h. After this time it was cooled to r.t.,and 1 mL of TFA was added. The reaction was stirred for additional 30min before it was diluted with MeOH and purified by prep-LCMS (XBridgeC18 column, eluting with a gradient of acetonitrile/water containing0.1% TFA, at flow rate of 60 mL/min). The product was isolated as theTFA salt. LC-MS calculated for C₂₇H₂₈N₇O₂ (M+H)+: m/z=482.2; found482.3.

Example 56.2-(3-(6-Methoxy-3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2-methylphenyl)acetonitrile

This compound was prepared according to the procedure described inExample 55, using4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholineinstead of1-(4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazin-1-yl)ethan-1-one.The product was isolated as the TFA salt. LC-MS calculated forC₂₅H₂₅N₆O₂ (M+H)⁺: m/z=441.2; found 441.2.

Example 57.5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-3-(6-(pyrrolidin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine

To a solution of5-(2,3-dihydro-1H-inden-4-yl)-3-iodo-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine(Example 53, step 3; 20 mg, 0.04 mmol) in 1,4-dioxane (0.5 mL) and water(0.1 mL) was added2-(pyrrolidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(13 mg, 0.047 mmol), potassium phosphate (17 mg, 0.078 mmol), and[dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (3 mg, 4 μmol). The reaction was degassed with N₂and stirred at 80° C. After 2 h, triflic acid (0.5 mL) was added to thereaction mixture at r.t. After 10 min, the reaction mixture was dilutedwith MeOH and purified by prep-LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min). The product was isolated as the TFA salt. LC-MS calculated forC₂₅H₂₆N₅O (M+H)+: m/z=412.2; found 412.2.

Example 58.4-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)morpholine

This compound was prepared according to the procedure described inExample 57, using4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholineinstead of2-(pyrrolidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine.The product was isolated as the TFA salt. LC-MS calculated forC₂₅H₂₆N₅O₂ (M+H)⁺: m/z=428.2; found 428.2. 1H NMR (600 MHz, DMSO-d6) δ13.20 (s, 1H), 9.18 (d, J=2.2 Hz, 1H), 8.55 (dd, J=9.1, 2.4 Hz, 1H),7.53 (s, 1H), 7.33-7.20 (m, 3H), 7.14 (s, 1H), 4.49 (bs, 3H), 3.85 (s,3H), 3.75 (t, J=4.9 Hz, 4H), 2.93 (t, J=7.4 Hz, 2H), 2.79 (t, J=7.3 Hz,2H), 2.48 (s, 1H), 1.98 (m, 2H) ppm.

Example 59.4-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-N-ethylpiperazine-1-carboxamide

Step 1.5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-3-(6-(piperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine

To a solution of5-(2,3-dihydro-1H-inden-4-yl)-3-iodo-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine(Example 53, step 3; 200 mg, 0.4 mmol) in 1,4-dioxane (5 mL) and water(1 mL) were added tert-butyl4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate(183 mg, 0.469 mmol), potassium phosphate (166 mg, 0.78 mmol), and[dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (32 mg, 0.039 mmol). The reaction was degassedwith N₂ and stirred at 80° C. for 8 h. After this time it was cooled tor.t., and 2 ml of TFA was added. The reaction was stirred for anadditional 30 min before dilution with EtOAc. The solution was washedsequentially with water, sat. NaCl and dried over Na₂SO₄. The organicphases were filtered and concentrated to dryness. The residue waspurified by Biotage Isolera to afford the desired product. LC-MScalculated for C₃₃H₃₅N₆O₂ (M+H)⁺: m/z=547.3; found 547.3.

Step 2.4-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-N-ethylpiperazine-1-carboxamide

To a solution of5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-3-(6-(piperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine(20 mg, 0.037 mmol) in DCM (1 ml) was added TEA (100, 0.073 mmol), andisocyanatoethane (3 mg, 0.040 mmol). The reaction was stirred at r.t.for 1 h before being concentrated to dryness. Triflic acid (0.5 ml) wasadded to the crude material and the reaction was stirred at r.t. for 10min. The reaction was then diluted with water and MeOH, then purified byprep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). Theproduct was isolated as the TFA salt. LCMS calculated for C₂₈H₃₂N₇O₂(M+H)⁺: m/z=498.2; found 498.3.

Example 60.4-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperazine-1-carboxamide

This compound was prepared according to the procedure described inExample 59, using isocyanatotrimethylsilane instead of isocyanatoethane.The product was isolated as the TFA salt. LC-MS calculated forC₂₆H₂₈N₇O₂ (M+H)⁺: m/z=470.2; found 470.2.

Example 61.1-(4-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)phenyl)piperazin-1-yl)ethan-1-one

This compound was prepared according to the procedure described inExample 57, using1-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazin-1-yl)ethan-1-oneinstead of2-(pyrrolidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine.The product was isolated as the TFA salt. LC-MS calculated forC₂₈H₃₀N₅O₂ (M+H)⁺: m/z=468.2; found 468.2.

Example 62.5-(2,3-Dihydro-1H-inden-4-yl)-3-(4-(4-isopropylpiperazin-1-yl)phenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine

This compound was prepared according to the procedure described inExample 57, using1-isopropyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazineinstead of2-(pyrrolidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine.The product was isolated as the TFA salt. LC-MS calculated for C₂₉H₃₄N₅O(M+H)⁺: m/z=468.3; found 468.3.

Example 63.5-(2,3-Dihydro-1H-inden-4-yl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine

This compound was prepared according to the procedure described inExample 57, using1-ethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazineinstead of2-(pyrrolidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine.The product was isolated as the TFA salt. LC-MS calculated for C₂₈H₃₂N₅O(M+H)⁺: m/z=454.3; found 454.3.

Example 64.1-(4-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperazin-1-yl)ethan-1-one

This compound was prepared according to the procedure described inExample 57, using1-(4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazin-1-yl)ethan-1-oneinstead of2-(pyrrolidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine.The product was isolated as the TFA salt. LC-MS calculated forC₂₇H₂₉N₆O₂ (M+H)⁺: m/z=469.2; found 469.2.

Example 65.8-(5-(5-(2,3-Dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one

This compound was prepared according to the procedure described inExample 45, using 1-oxa-3,8-diazaspiro[4.5]decan-2-one hydrochlorideinstead of 1-methylpiperazin-2-one hydrochloride. The product wasisolated as the TFA salt. LC-MS calculated for C₂₇H₂₉N₆O₃ (M+H)⁺:m/z=485.2; found 485.2.

Example 66.5-(2,3-Dimethylphenyl)-6-methoxy-3-(1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine

Step 1. 6-Bromo-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine

6-Bromo-1H-pyrazolo[4,3-b]pyridine (10 g, 50.5 mmol),1-(chloromethyl)-4-methoxybenzene (8.7 g, 55.5 mmol), potassiumcarbonate (7.68 g, 55.5 mmol) were placed in a round bottom flask. AfterDMF (168 ml) was added, the reaction mixture was stirred at 80° C. for 4h. After this time it was cooled to r.t., diluted with water andextracted with EtOAc 3 times. The combined organic phases were washedwith sat. NaCl solution, dried over Na₂SO₄, filtered and concentrated todryness. The residue was purified by silica gel chromatography to affordthe desired product. LC-MS calculated for C₁₄H₁₃BrN₃O (M+H)⁺: m/z=318.2;found 318.2.

Step 2. 6-Methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine

To a 250 mL round bottom flask was added Cs₂CO₃ (4.67 g, 14.3 mmol),t-butyl XPhos Pd G3 (0.47 g, 0.6 mmol), MeOH (10 ml), toluene (50 ml)and 6-bromo-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine (3.8 g, 11.9mmol). The mixture was evacuated and backfilled with N₂ three times andheated at 100° C. for 4 h. The resulting mixture was filtered andconcentrated to dryness. The residue was purified by Biotage Isolera toafford the desired product. LC-MS calculated for C₁₅H₁₆N₃O₂ (M+H)⁺:m/z=270.1; found 270.1.

Step 3. 6-Methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine 4-oxide

To a solution of6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine (13.3 g, 49.3mmol) in DCM (100 ml) cooled in water bath was added3-chlorobenzoperoxoic acid (16.6 g, 74 mmol). The reaction was stirredat r.t. for 2 h. The mixture was washed with Na₂S₂O₃ saturated solution,followed by NaHCO₃ saturated solution. The combined organic phases werewashed with sat. NaCl, dried over Na₂SO₄, filtered and concentrated todryness. The residue was purified by silica gel chromatography to affordthe desired product. LC-MS calculated for C₁₅H₁₆N₃O₃ (M+H)⁺: m/z=286.2;found 286.2.

Step 4.5-Chloro-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine

To a solution of6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine 4-oxide (12 g,42.1 mmol) in DCM (90 ml) was added N,N-diisopropylethylamine (10.9 g,84 mmol). The mixture was cooled in the ice bath and oxalyl chloride(8.01 g, 63.1 mmol) was added. The resulting mixture was stirred at 0°C. for 1 h before being quenched with saturated NaHCO₃ solution. Theproduct was extracted with DCM, the combined organic phases were washedwith sat. NaCl solution, dried over Na₂SO₄, filtered and concentrated todryness. The residue was purified by Biotage Isolera to afford thedesired product. LC-MS calculated for C₁₅H₁₅ClN₃O₂ (M+H)⁺: m/z=304.1;found 304.1.

Step 5.5-(2,3-Dimethylphenyl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine

5-Chloro-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine (3.5g, 11.52 mmol), (2,3-dimethylphenyl)boronic acid (2.07 g, 13.83 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(0.90 g, 1.15 mmol) and cesium carbonate (7.51 g, 23.05 mmol) wereplaced in a round bottom flask and the flask was evacuated andbackfilled with N₂ three times. After 1,4-dioxane (32 ml) and water (6.4ml) were added, the reaction mixture was stirred at 100° C. for 1 h.After this time it was cooled to r.t., diluted with water and extractedwith EtOAc 3 times. The combined organic phases were washed with sat.NaCl solution, dried over Na₂SO₄, filtered and concentrated to dryness.The residue was purified by Biotage Isolera to afford the desiredproduct. LC-MS calculated for C₂₃H₂₄N₃O₂ (M+H)⁺: m/z=374.2; found 374.2.

Step 6.5-(2,3-Dimethylphenyl)-3-iodo-6-methoxy-1H-pyrazolo[4,3-b]pyridine

5-(2,3-Dimethylphenyl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine(3.87 g, 10.36 mmol) was dissolved in TFA (12 ml). The mixture washeated to 100° C. for 1 h before it was cooled to 0° C. and neutralizedwith 4N NaOH aqueous solution. The product was extracted with DCM (50ml×3) and the combined organic phases were washed with sat. NaClsolution, dried over Na₂SO₄, filtered and concentrated to dryness. Tothe residue was added NIS (2.56 g, 11.4 mmol) and DMF (20 ml). Theresulting mixture was heated to 80° C. for 2 h. After this time it wascooled to r.t., diluted with water and extracted with EtOAc 3 times. Thecombined organic phases were washed with sat. NaCl solution, dried overNa₂SO₄, filtered and concentrated to dryness. The residue was useddirectly in the next step without purification. LC-MS calculated forC₁₅H₁₅IN₃O (M+H)⁺: m/z=380.2; found 380.2.

Step 7. tert-Butyl5-(2,3-dimethylphenyl)-3-iodo-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate

To a solution of5-(2,3-dimethylphenyl)-3-iodo-6-methoxy-1H-pyrazolo[4,3-b]pyridine (1.9g, 5.01 mmol) in DMF (10 ml) was added di-tert-butyl dicarbonate (2.19g, 10.02 mmol), triethylamine (1.27 g, 12.53 mmol) and4-dimethylaminopyridine (6 mg, 0.05 mmol). The resulting mixture wasstirred at r.t. for 2 h. After this time it was diluted with water andextracted with EtOAc 3 times. The combined organic phases were washedwith sat. NaCl solution, dried over Na₂SO₄, filtered and concentrated todryness. The residue was purified by Biotage Isolera to afford thedesired product. LC-MS calculated for C₂₀H₂₃IN₃O₃ (M+H)⁺: m/z=480.2;found 480.2.

Step 8.5-(2,3-Dimethylphenyl)-6-methoxy-3-(1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine

To a solution of tert-butyl5-(2,3-dimethylphenyl)-3-iodo-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate(15 mg, 0.031 mmol) in 1,4-dioxane (0.5 mL) and water (0.05 mL) wereadded2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)pyridine(18 mg, 0.063 mmol), potassium phosphate (19.9 mg, 0.094 mmol), andchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(2.5 mg, 0.003 mmol). The reaction was degassed with N₂ and stirred at80° C. for 3 h. After this time it was cooled to r.t., diluted withEtOAc, washed sequentially with water, sat. NaCl and dried over Na₂SO₄.The organic phases were combined, filtered and concentrated to dryness.The residue was dissolved in 4N HCl in dioxane (1 ml) and the resultingmixture was stirred at r.t. After 10 min, the reaction mixture wasdiluted with MeOH and was purified by prep-LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min). The product was isolated as the TFA salt. LC-MScalculated for C₂₄H₂₃N₆O (M+H)+: m/z=411.2; found 411.2.

Example 67.3-(1-Cyclopropyl-1H-pyrazol-4-yl)-5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine

This compound was prepared according to the procedure described inExample 66, using1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleinstead of2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)pyridineas starting material. The product was isolated as the TFA salt. LC-MScalculated for C₂₁H₂₂N₅O (M+H)⁺: m/z=360.2; found 360.2.

Example 68.6-Methoxy-5-(2-methyl-3-(methyl-d3)phenyl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine

Step 1. 1-Bromo-2-methyl-3-(methyl-d3)benzene

To a solution of 1-bromo-3-iodo-2-methylbenzene (300 mg, 1 mmol) in THF(3 mL) at −20° C. was slowly added isopropylmagnesium chloride solution2.0 M in THF (0.76 ml, 1.5 mmol). The reaction mixture was stirred at 0°C. for 1 h before iodomethane-d3 was added. The mixture was stirred atr.t. overnight and then diluted with EtOAc. The mixture was washedsequentially with water and sat. NaCl solution and dried over Na₂SO₄.The organic phases were filtered and concentrated to dryness. Theresidue was purified by Biotage Isolera to afford the desired product.

Step 2.4,4,5,5-Tetramethyl-2-(2-methyl-3-(methyl-d3)phenyl)-1,3,2-dioxaborolane

To a solution of 1-bromo-2-methyl-3-(methyl-d3)benzene (112 mg, 0.6mmol) in 1,4-dioxane (4 ml) were added bis(pinacolato)diboron (302 mg,1.19 mmol), potassium acetate (175 mg, 1.79 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1:1) (49mg, 0.06 mmol). The reaction was purged with N₂ and stirred at 90° C.for 12 h. After this time it was cooled to r.t. and diluted with EtOAc.It was then washed sequentially with water, sat. NaCl solution and driedover Na₂SO₄. The organic phases were filtered and concentrated todryness. The residue was purified by Biotage Isolera to afford thedesired product. LC-MS calculated for C₁₄H₁₉D₃BO₂ (M+H)+: m/z=236.2;found 236.2.

Step 3.6-Methoxy-1-(4-methoxybenzyl)-5-(2-methyl-3-(methyl-d3)phenyl)-1H-pyrazolo[4,3-b]pyridine

5-Chloro-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine (155mg, 0.51 mmol),4,4,5,5-tetramethyl-2-(2-methyl-3-(methyl-d3)phenyl)-1,3,2-dioxaborolane(100 mg, 0.43 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(33 mg, 0.043 mmol) and cesium carbonate (277 mg, 0.85 mmol) were placedin a round bottom flask and the flask was evacuated and backfilled withN₂ three times. After 1,4-dioxane (2.5 ml) and water (0.5 ml) wereadded, the reaction mixture was stirred at 100° C. for 1 h. The reactionmixture was cooled to r.t., diluted with water and extracted with EtOAc3 times. The combined organic phases were washed with sat. NaClsolution, dried over Na₂SO₄, filtered and concentrated to dryness. Theresidue was purified by Biotage Isolera to afford the desired product.

LC-MS calculated for C₂₃H₂₁D₃N₃O₂ (M+H)⁺: m/z=377.2; found 377.2.

Step 4.3-Iodo-6-methoxy-5-(2-methyl-3-(methyl-d3)phenyl)-1H-pyrazolo[4,3-b]pyridine

6-Methoxy-1-(4-methoxybenzyl)-5-(2-methyl-3-(methyl-d3)phenyl)-1H-pyrazolo[4,3-b]pyridine(0.3 g, 0.8 mmol) was dissolved in TFA (1 ml). The mixture was heated to100° C. for 1 h and then cooled to 0° C. and neutralized with 4N NaOHaqueous solution. The product was extracted with DCM (5 ml×3) and thecombined organic phases were washed with sat. NaCl solution, dried overNa₂SO₄, filtered and concentrated to dryness.

To the residue was added MS (0.18 g, 0.8 mmol) and DMF (4 ml). Theresulting mixture was heated to 80° C. for 2 h. After this time it wascooled to r.t., diluted with water and extracted with EtOAc 3 times. Thecombined organic phases were washed with sat. NaCl solution, dried overNa₂SO₄, filtered and concentrated to dryness. The residue was useddirectly in the next step without purification. LC-MS calculated forC₁₅H₁₂D₃IN₃O (M+H)⁺: m/z=383.2; found 383.2.

Step 5.3-Iodo-6-methoxy-5-(2-methyl-3-(methyl-d3)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine

To a solution of3-iodo-6-methoxy-5-(2-methyl-3-(methyl-d3)phenyl)-1H-pyrazolo[4,3-b]pyridine(306 mg, 0.8 mmol) in DMF (4 ml) was added2-(trimethylsilyl)ethoxymethyl chloride (0.2 g, 1.2 mmol) and cesiumcarbonate (0.52 g, 1.6 mmol). The resulting mixture was stirred at 80°C. for 1 h. After this time the mixture was diluted with water andextracted with EtOAc 3 times. The combined organic phases were washedwith sat. NaCl solution, dried over Na₂SO₄, filtered and concentrated todryness. The residue was used directly in the next step withoutpurification. LC-MS calculated for C₂₁H₂₆D₃IN₃O₂Si (M+H)⁺: m/z=513.2;found 513.2.

Step 6.6-Methoxy-5-(2-methyl-3-(methyl-d3)phenyl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine

To a solution of3-iodo-6-methoxy-5-(2-methyl-3-(methyl-d3)phenyl)-1-((2-(trimethylsilyl)-ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine(60 mg, 0.12 mmol) in 1,4-dioxane (1 mL) and water (0.1 mL) were added1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine(71 mg, 0.23 mmol), potassium phosphate (75 mg, 0.35 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1:1) (10mg, 0.012 mmol). The reaction was purged with N₂ and stirred at 80° C.for 2 h. The mixture was cooled to r.t. and diluted with EtOAc. It wasthen washed sequentially with water, sat. NaCl solution and dried overNa₂SO₄. The organic phases were filtered and concentrated to dryness.The residue was dissolved in TFA (0.5 ml) and stirred at r.t. for 1 h.The mixture was concentrated and ammonium hydroxide solution (0.5 ml)was added. The reaction mixture was stirred at r.t. for 1 h and thenconcentrated. The residue was dissolved in MeOH and purified byprep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). Theproduct was isolated as the TFA salt. LC-MS calculated for C₂₅H₂₆D₃N₆O(M+H)⁺: m/z=432.2; found 432.2. ¹H NMR (400 MHz, DMSO-d6) δ 9.23-9.18(d, J=2.3 Hz, 1H), 8.53-8.46 (dd, J=8.9, 2.4 Hz, 1H), 7.54-7.49 (s, 1H),7.26-7.21 (d, J=1.6 Hz, 1H), 7.20-7.14 (t, J=7.5 Hz, 1H), 7.12-7.06 (m,2H), 4.50-4.42 (d, J=13.2 Hz, 2H), 3.87-3.82 (s, 3H), 3.22-3.05 (dt,J=24.7, 12.1 Hz, 4H), 2.88-2.82 (d, J=3.7 Hz, 3H), 2.00-1.95 (s, 3H)ppm.

Example 69.1-(4-(4-(5-(2,3-Dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethan-1-one

Step 1.5-(2,3-Dimethylphenyl)-3-iodo-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine

To a solution of5-(2,3-dimethylphenyl)-3-iodo-6-methoxy-1H-pyrazolo[4,3-b]pyridine(Example 66, 1.9 g, 5.01 mmol) in DMF (10 ml) was added1-(chloromethyl)-4-methoxybenzene (1.02 g, 6.51 mmol) and potassiumcarbonate (1.04 g, 7.52 mmol). The resulting mixture was stirred at 80°C. for 1 h. After this time it was diluted with water and the productwas extracted with EtOAc 3 times. The combined organic phases werewashed with sat. NaCl solution, dried over Na₂SO₄, filtered andconcentrated to dryness. The residue was used directly in the next stepwithout purification. LC-MS calculated for C₂₃H₂₃IN₃O₂ (M+H)⁺:m/z=500.2; found 500.2.

Step 2. tert-butyl4-(4-(5-(2,3-Dimethylphenyl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

To a solution of5-(2,3-dimethylphenyl)-3-iodo-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine(150 mg, 0.3 mmol) in 1,4-dioxane (3 mL) and water (0.3 mL) was addedtert-butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(227 mg, 0.6 mmol), potassium phosphate (191 mg, 0.9 mmol), andchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(24 mg, 0.03 mmol). The reaction was degassed with N₂ and stirred at 80°C. for 3 h. After this time it was cooled to r.t. and was diluted withEtOAc. The resultant solution was washed sequentially with water, sat.NaCl solution and dried over Na₂SO₄. The organic phases were filteredand concentrated to dryness. The residue was purified by Biotage Isolerato afford the desired product. LC-MS calculated for C₃₆H₄₃N₆O₄ (M+H)+:m/z=623.2; found 623.2.

Step 3.5-(2,3-Dimethylphenyl)-6-methoxy-1-(4-methoxybenzyl)-3-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine

tert-Butyl4-(4-(5-(2,3-dimethylphenyl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(156 mg, 0.3 mmol) was dissolved in 4N HCl in dioxane (3 ml) and theresulting mixture was stirred at r.t. After 10 min, the reaction mixturewas concentrated to dryness and the crude was used directly for the nextstep. LC-MS calculated for C₃₁H₃₅N₆O₂ (M+H)⁺: m/z=523.2; found 523.2.

Step 4.1-(4-(4-(5-(2,3-Dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethan-1-one

To a solution of5-(2,3-dimethylphenyl)-6-methoxy-1-(4-methoxybenzyl)-3-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine(10 mg, 0.019 mmol) in DCM (0.5 ml) was added N,N-diisopropylethylamine(24 mg, 0.19 mmol) and acetyl chloride (7.5 mg, 0.096 mmol). Thereaction mixture was stirred at r.t. for 1 h. After this time it wasdiluted with EtOAc, washed sequentially with water, sat. NaCl solutionand dried over Na₂SO₄. The organic phase was filtered and concentratedto dryness. The residue was dissolved in DCM (0.5 ml) and triflic acid(0.5 ml). After 30 min, the reaction mixture was diluted with MeOH thenpurified by prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). Theproduct was isolated as the TFA salt. LC-MS calculated for C₂₅H₂₉N₆O₂(M+H)+: m/z=445.2; found 445.2.

Example 70. Methyl4-(4-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

This compound was prepared according to the procedure described inExample 69, using methyl carbonochloridate instead of acetyl chloride asstarting material. The product was isolated as the TFA salt. LC-MScalculated for C₂₅H₂₉N₆O₃ (M+H)⁺: m/z=461.2; found 461.2.

Example 71. Methyl3-(4-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate

Step 1. tert-Butyl3-(4-(5-(2,3-dimethylphenyl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate

To a solution of5-(2,3-dimethylphenyl)-3-iodo-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine(example 69, 150 mg, 0.3 mmol) in 1,4-dioxane (3 mL) and water (0.3 mL)were added tert-butyl3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate(210 mg, 0.6 mmol), potassium phosphate (191 mg, 0.9 mmol), andchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(24 mg, 0.03 mmol). The reaction was degassed with N₂ and stirred at 80°C. for 3 h. After this time it was cooled to r.t. before being dilutedwith EtOAc. It was then washed sequentially with water, sat. NaClsolution and dried over Na₂SO₄. The organic phases were filtered andconcentrated to dryness. The residue was purified by Biotage Isolera toafford the desired product. LC-MS calculated for C₃₄H₃₉N₆O₄ (M+H)+:m/z=595.2; found 595.2.

Step 2.3-(1-(Azetidin-3-yl)-1H-pyrazol-4-yl)-5-(2,3-dimethylphenyl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine

tert-Butyl3-(4-(5-(2,3-dimethylphenyl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate(178 mg, 0.3 mmol) was dissolved in 4N HCl in dioxane (3 ml) and theresulting mixture was stirred at r.t. After 10 min, the reaction mixturewas concentrated to dryness and the crude was used directly in the nextstep. LC-MS calculated for C₂₉H₃₁N₆O₂ (M+H)⁺: m/z=495.2; found 495.2.

Step 3. Methyl3-(4-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate

To a solution of3-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-5-(2,3-dimethylphenyl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine(10 mg, 0.02 mmol) in DCM (0.5 ml) was added N,N-diisopropylethylamine(24 mg, 0.19 mmol) and methyl carbonochloridate (9 mg, 0.096 mmol). Themixture was stirred at r.t. for 1 h. After this time it was diluted withEtOAc, washed sequentially with water, sat. NaCl solution and dried overNa₂SO₄. The organic phases were filtered and concentrated to dryness.The residue was dissolved in DCM (0.5 ml) and triflic acid (0.5 ml).After 30 min, the reaction mixture was diluted with MeOH and purified byprep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). Theproduct was isolated as the TFA salt. LC-MS calculated for C₂₃H₂₅N₆O₃(M+H)⁺: m/z=433.2; found 433.2.

Example 72.3-(4-(5-(2,3-Dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)-N,N-dimethylazetidine-1-carboxamide

To a solution of3-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-5-(2,3-dimethylphenyl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine(Example 71, 10 mg, 0.02 mmol) in DCM (0.5 ml) was addedN,N-diisopropylethylamine (24 mg, 0.19 mmol) and dimethylcarbamicchloride (11 mg, 0.1 mmol). The mixture was stirred at r.t. for 1 h.After this time it was diluted with EtOAc, washed sequentially withwater, sat. NaCl solution and dried over Na₂SO₄. The organic phases werefiltered and concentrated to dryness. The residue was dissolved in DCM(0.5 ml) and triflic acid (0.5 ml). After 30 min, the reaction mixturewas diluted with MeOH then purified by prep-LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min). The product was isolated as the TFA salt. LC-MScalculated for C₂₄H₂₈N₇O₂ (M+H)⁺: m/z=446.2; found 446.2. ¹H NMR (500MHz, DMSO-d6) δ 8.53-8.31 (s, 1H), 8.26-8.10 (s, 1H), 7.55-7.40 (s, 1H),7.24-7.19 (d, J=8.1 Hz, 1H), 7.19-7.13 (t, J=7.5 Hz, 1H), 7.11-7.07 (dd,J=7.4, 1.7 Hz, 1H), 5.47-5.24 (m, 1H), 4.32-4.26 (t, J=8.4 Hz, 2H),4.26-4.20 (dd, J=8.7, 5.9 Hz, 2H), 3.91-3.70 (s, 3H), 2.82-2.76 (s, 6H),2.36-2.27 (s, 3H), 2.01-1.92 (s, 3H) ppm.

Example 73.4-(6-Methoxy-3-(6-((tetrahydrofuran-3-yl)oxy)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-2-ol

Step 1. tert-Butyl5-(2-hydroxy-2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate

tert-Butyl 5-chloro-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate(2.00 g, 7.05 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-ol(2.2 g, 8.46 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(120 mg, 0.15 mmol) and potassium phosphate (4.6 g, 14.1 mmol) wereplaced in a flask and the flask was evacuated and backfilled with N₂three times. After 1,4-dioxane (20 ml) and water (4 ml) were added, thereaction mixture was stirred at 80° C. for 2 hs. After cooling to r.t.,water was added and the desired product was extracted with EtOAc. Theorganic phase was washed with brine, dried over sodium sulfate and thesolvent was evaporated in vacuo. Crude material was purified by BiotageIsolera to give a white solid (2.40 g, 89%). LCMS calculated forC₂₁H₂₄N₃O₄ (M+H)⁺: m/z=382.2; found 382.2.

Step 2.4-(6-Methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-2-ol

tert-Butyl5-(2-hydroxy-2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate(2.40 g, 6.29 mmol) in a mixture of DCM (20 ml) and TFA (10 ml) wasstirred at r.t. for 1 h. The reaction mixture was then concentrated invacuo, dissolved in DCM and neutralized with NaHCO₃ solution. Theorganic phase was separated, dried over sodium sulfate and concentratedin vacuo. Crude material was used in the next step without furtherpurification. LCMS calculated for C₁₆H₁₆N₃O₂ (M+H)⁺: m/z=282.1; found282.1.

Step 3. tert-Butyl5-(2-hydroxy-2,3-dihydro-1H-inden-4-yl)-3-iodo-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate

NIS (2.1 g, 9.38 mmol) was added to a solution of4-(6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-2-ol(2.40 g, 8.53 mmol) in DMF (20 ml). After stirring at 80° C. for 2 hrs,the reaction mixture was cooled to r.t., and triethylamine (1.50 ml,10.5 mmol) and Boc-anhydride (2.30 g, 10.5 mmol) were added. Afteradditional stirring at r.t. for 1 hr, water was added and theprecipitated product was collected by filtration and air dried. Thecrude material was purified by Biotage Isolera to give a white solid.LCMS calculated for C₂₁H₂₃IN₃O₄ (M+H)⁺: m/z=508.3; found 508.3.

The two enantiomers were separated with chiral prep-HPLC (Phenomenex LUXAmylose Sum 21.2×250 mm, eluting with 35% MeOH (containing 2 mM NH₃) inCO₂, at flow rate of 70 mL/min, t_(R, peak 1)=2.9 min, t_(R, peak 2)=3.6min). Peak 2 was collected and the solvents were evaporated in vacuo.

Step 4. tert-Butyl5-(2-hydroxy-2,3-dihydro-1H-inden-4-yl)-6-methoxy-3-(6-((tetrahydrofuran-3-yl)oxy)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine-1-carboxylate

tert-Butyl5-(2-hydroxy-2,3-dihydro-1H-inden-4-yl)-3-iodo-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate(100 mg, 0.197 mmol),2-((tetrahydrofuran-3-yl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(68.9 mg, 0.237 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(17 mg, 22 μmol) and potassium phosphate (85 mg, 0.40 mmol) were placedin a vial and the vial was evacuated and backfilled with N₂ three times.After 1,4-dioxane (5 ml) and water (1.0 ml) were added, the reactionmixture was stirred at 80° C. for 2 hs. After cooling to r.t., water wasadded and the desired product was extracted with EtOAc. The organicphase was washed with brine, dried over sodium sulfate and the solventwas evaporated in vacuo. Crude material was purified by Biotage Isolerato give a white solid (90 mg, 84%). LCMS calculated for C₃₀H₃₃N₄O₆(M+H)⁺: m/z=545.2; found 545.2.

Step 5.4-(6-Methoxy-3-(6-((tetrahydrofuran-3-yl)oxy)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-2-ol

The two enantiomers of tert-butyl5-(2-hydroxy-2,3-dihydro-1H-inden-4-yl)-6-methoxy-3-(6-((tetrahydrofuran-3-yl)oxy)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine-1-carboxylate(90 mg, 0.197 mmol) were separated with chiral prep-HPLC (Phenomenex LUXi-Cellulose-5 5 um 21.2×250 mm, eluting with 35% MeOH (2 nM NH₃) in CO₂,at flow rate of 65 mL/min, t_(R, peak 1)=11.1 min t_(R, peak 2)=12.4min). Peak 2 was collected and the solvents were evaporated in vacuo.The resultant material was dissolved in 1,4-dioxane (2 ml) and water (2ml). After addition of cesium carbonate (31.3 mg, 0.096 mmol), thereaction mixture was heated at 100° C. for 2 hrs. After cooling to roomtemperature, the mixture was diluted with CH₃CN and purified byprep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). Theproduct was isolated as the TFA salt. LCMS calculated for C₂₅H₂₅N₄O₄(M+H)⁺: m/z=445.2; Found: 445.2.

Example 74.4-(6-Methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)2,3-dihydro-1H-inden-2-d-2-ol

Step 1. 4-Bromo-2,3-dihydro-1H-inden-2-d-2-ol

Sodium borodeuteride (0.397 g, 9.48 mmol) was added to a solution of4-bromo-1,3-dihydro-2H-inden-2-one (1.00 g, 4.74 mmol) in THF (5 ml) andMeOH (5 ml). After the reaction mixture was stirred at r.t. for 1 h,water was added. The desired product was extracted with EtOAc, theorganic phase was washed with brine, dried over sodium sulfate and thesolvents were evaporated in vacuo. The resultant crude product was usedin the next step without further purification.

Step 2.4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-d-2-ol

This compound was prepared according to the procedures described inIntermediate 2, using 4-bromo-2,3-dihydro-1H-inden-2-d-2-ol instead of4-bromo-2,3-dihydro-1H-inden-1-ol as starting material.

Step 3.4-(6-Methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)2,3-dihydro-JH-inden-2-d-2-ol

tert-Butyl5-chloro-6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine-1-carboxylate(1.05 g, 2.89 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-d-2-ol(0.904 g, 3.46 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(150 mg, 0.20 mmol) and potassium phosphate (150 mg, 7.00 mmol) wereplaced in a vial and the vial was evacuated and backfilled with N₂ threetimes. After 1,4-dioxane (10.0 ml) and water (2.0 ml) were added, thereaction mixture was stirred at 100° C. for 1 h. After cooling to roomtemperature, the mixture was diluted with DCM and filtered. The filtratewas concentrated in vacuo and the resultant residue was purified byBiotage Isolera.

The two enantiomers were separated with chiral prep-HPLC (Phenomenex LUXCellulose-1 Sum 21.2×250 mm, eluting with 10% EtOH in CO₂, at flow rateof 65 mL/min, t_(R, peak 1)=19.5 min, t_(R, peak 2)=21.8 min). Peak 2was collected and the solvents were evaporated in vacuo.

The resultant material was dissolved in 1,4-dioxane (2 ml) and water (2ml). After addition of cesium carbonate (31.3 mg, 0.096 mmol) thereaction mixture was heated at 100° C. for 2 h. After cooling to roomtemperature, the mixture was diluted with CH₃CN and purified byprep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). Theproduct was isolated as the TFA salt. LCMS calculated for C₂₀DH₁₉N₅O₂(M+H)⁺: m/z=363.2; Found: 363.2. ¹H NMR (500 MHz, DMSO-d6) δ 8.35 (s,1H), 8.08 (s, 1H), 7.50 (s, 1H), 7.34-7.28 (d, J=7.2 Hz, 1H), 7.29-7.20(m, 2H), 3.90 (s, 3H), 3.84 (s, 3H), 3.16-3.11 (d, J=16.0, 1H),3.08-3.00 (d, J=16.0, 1H), 2.88-2.80 (d, J=16.0, 1H), 2.70-2.64 (d,J=16.0, 1H) ppm.

Example 75.4-(6-Methoxy-3-(6-(1-methyl-5-oxopyrrolidin-3-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile

Step 1. tert-Butyl4-(5-bromopyridin-2-yl)-2-oxopyrrolidine-1-carboxylate

A 30-mL screw-top vial equipped with a stir bar was charged with diethyl2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (413 mg, 1.629 mmol),5-bromo-2-iodopyridine (300 mg, 1.057 mmol),[Ir{dF(CF₃)ppy}₂(dtbbpy)]PF₆ (28.1 mg, 0.025 mmol), and tert-butyl2-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate (689 mg, 3.76 mmol). The vialwas sealed and the atmosphere was exchanged by applying vacuum andbackfilling with N₂. Under N₂ atmosphere, the tube was charged withdegassed solvent (3:1 DMSO:H₂O, 15 mL) via syringe. The resultingsuspension was stirred under irradiation with blue LEDs for 18 hours.The reaction mixture was then treated with saturated sodium bicarbonatesolution (60 mL) and extracted with ethyl acetate (3×40 mL). The organicphases were combined, dried over magnesium sulfate, filtered, andconcentrated under vacuum. The residue was purified by flash columnchromatography to afford the desired product. LC-MS calculated forC₁₄H₁₈BrN₂O₃ (M+H)⁺: m/z=341.0; found 341.0.

Step 2. 4-(5-Bromopyridin-2-yl)-1-methylpyrrolidin-2-one

tert-Butyl 4-(5-bromopyridin-2-yl)-2-oxopyrrolidine-1-carboxylate (294mg, 0.865 mmol) was dissolved in 1 mL of TFA and the resulting mixturewas stirred at r.t. After 10 min, the reaction mixture was concentratedto dryness. The resultant residue was taken up in 2 mL of DMF and cooledto 0° C. with an ice bath. Sodium hydride (41.5 mg, 1.73 mmol) wasadded, and the resulting solution was stirred at 0° C. for 30 min. Mel(108 μl, 1.73 mmol) was then added, and the resulting mixture was warmedto r.t. and stirred for 2 hrs. The reaction was treated with saturatedNH₄Cl solution and extracted with DCM. The organic phases were combined,dried over magnesium sulfate, filtered, and concentrated under vacuum.The residue was purified by flash column chromatography to afford thedesired product. LC-MS calculated for C₁₀H₁₂BrN₂O (M+H)+: m/z=255.0;found 255.0.

The two enantiomers were separated with chiral prep-HPLC (Phenomenex LUXAmylose-1 Sum 21.2×250 mm, eluting with 35% MeOH in CO₂, at flow rate of65 mL/min, t_(R, peak 1=3.6) min, t_(R, peak 2)=4.7 min)

Step 3.1-Methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrrolidin-2-one

Two enantiomers of 4-(5-bromopyridin-2-yl)-1-methylpyrrolidin-2-one (60mg, 0.235 mmol) were individually added to mixture ofbis(pinacolato)diboron (65.7 mg, 0.259 mmol), potassium acetate (69.2mg, 0.706 mmol), and PdCl₂(dppf)-CH₂Cl₂ adduct (19.21 mg, 0.024 mmol) in1,4-dioxane (1 mL). The mixture was heated to 100° C. for 8 h. Afterthis time, it was cooled to r.t. The crude product solution was useddirectly in the next step without further purification. LCMS calculatedfor C₁₆H₂₄BN₂O₃ (M+H)⁺: m/z=303.2; found 303.2.

Step 4. 4-Bromo-2,3-dihydro-1H-indene-1-carbonitrile

To a solution of 4-bromo-2,3-dihydro-1H-inden-1-one (10 g, 47.4 mmol) inDME (250 mL) and ^(t)BuOH (40 mL) was added potassium tert-butoxide(10.63 g, 95 mmol) and tosylmethylisocyanide (11.10 g, 56.9 mmol) at 0°C. The mixture was stirred overnight before being treated with water and1N HCl. The mixture was extracted with EtOAc, the organic phases werecombined, dried over magnesium sulfate, filtered, and concentrated undervacuum. The residue was purified by flash column chromatography toafford the desired product. LC-MS calculated for C₁₀H₉BrN (M+H)⁺:m/z=222.0; found 222.2.

Step 5.4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indene-1-carbonitrile

A mixture of 4-bromo-2,3-dihydro-1H-indene-1-carbonitrile (5.8 g, 26.5mmol), potassium acetate (7.81 g, 80 mmol), bis(pinacolato)diboron (8.09g, 31.8 mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (1.083 g, 1.327 mmol) in1,4-dioxane (100 mL) was heated to 100° C. for 8 h. After this time, itwas cooled to r.t. The crude product solution was used directly infollowing step without further purification. LCMS calculated forC₁₆H₂₁BNO₂ (M+H)⁺: m/z=270.2; found 270.2.

Step 6.4-(6-Methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile

5-Chloro-6-methoxy-1-trityl-1H-pyrazolo[4,3-b]pyridine (Example 1, step4) (8.52 g, 20 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indene-1-carbonitrile(6.46 g, 24.00 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(0.80 g, 1.0 mmol) and K₃PO₄ (8.48 g, 40.0 mmol) were placed in a roundbottom flask and the flask was evacuated and backfilled with N₂ threetimes. After 1,4-dioxane (30 mL) and water (6 mL) were added, thereaction mixture was stirred at 100° C. for 1 h. After this time, it wascooled to r.t., diluted with water and extracted with EtOAc 3 times. Thecombined organic phases were washed with sat. NaCl solution, dried overNa₂SO₄, filtered and concentrated to dryness. To the residue was added20 mL of TFA, the solution was cooled to 0° C. before triethylsilane(6.39 ml, 40.0 mmol) was added slowly. The resulting solution wasstirred at rt. for 4 h, then concentrated to dryness, washed with sat.NaHCO₃ and extracted with EtOAc. The combined organic phases were washedwith sat. NaCl solution, dried over Na₂SO₄, filtered and concentrated todryness and purified by flash column chromatography to afford thedesired product. LC-MS calculated for C₁₇H₁₅N₄O (M+H)⁺: m/z=291.1; found291.1.

Step 7. tert-Butyl5-(1-cyano-2,3-dihydro-1H-inden-4-yl)-3-iodo-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate

NIS (4.26 g, 18.94 mmol) was added to a solution of4-(6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile(5.0 g, 17.22 mmol) in DMF (60 ml). After stirring at 60° C. for 2 h,the reaction mixture was cooled to r.t., and DIEA (6.02 ml, 34.4 mmol)and Boc-anhydride (5.64 g, 25.8 mmol) were added. After additionalstirring at r.t. for 1 h, water was added and the product was extractedwith EtOAc. The combined organic phases were washed with sat. NaClsolution, dried over Na₂SO₄, filtered, concentrated to dryness andpurified by flash column chromatography to afford the desired product.LC-MS calculated for C₂₂H₂₂IN₄O₃ (M+H)⁺: m/z=517.1; found 517.1.

Step 8.4-(6-Methoxy-3-(6-(1-methyl-5-oxopyrrolidin-3-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile

tert-Butyl5-(1-cyano-2,3-dihydro-1H-inden-4-yl)-3-iodo-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate(50 mg, 0.097 mmol),1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrrolidin-2-one(peak 1 from step 5, 35.1 mg, 0.116 mmol), PdCl₂(dppf)-CH₂Cl₂ adduct(7.91 mg, 9.68 μmol), and K₃PO₄ (41.1 mg, 0.194 mmol) were placed in avial and the vial was evacuated and backfilled with N₂ three times.After 1,4-dioxane (1 ml) and water (100 μl) were added, the reactionmixture was stirred at 80° C. for 1 h. Then the reaction was filtered,and the solvents were evaporated in vacuo. DCM (1 ml) and TFA (0.5 ml)were added and the reaction mixture was stirred at r.t. for 30 min. Themixture was then diluted with CH₃CN and water and purified withprep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). Theproduct was isolated as the TFA salt.

The product was washed with sat. NaHCO₃ and further separated withchiral prep-HPLC (Phenomenex Lux 5 um Cellulose-2, 21.2×250 mm, elutingwith 80% EtOH in hexane, at flow rate of 20 mL/min, t_(R, peak 1)=13min, t_(R, peak 2)=16 min). Peak 1 is the desired product. LCMScalculated for C₂₇H₂₅N₆O₂ (M+H)⁺: m/z=465.2; Found: 465.2. ¹H NMR (500MHz, DMSO-d6) δ 13.46 (s, 1H), 9.55 (d, J=2.1 Hz, 1H), 8.68 (dd, J=8.2,2.2 Hz, 1H), 7.61 (s, 1H), 7.56-7.46 (m, 3H), 7.41 (t, J=7.5 Hz, 1H),4.58 (t, J=8.1 Hz, 1H), 3.91 (s, 3H), 3.86-3.71 (m, 2H), 3.52 (dd,J=9.2, 6.4 Hz, 1H), 3.02-2.84 (m, 2H), 2.77 (s, 3H), 2.68-2.53 (m, 3H),2.21 (dq, J=12.5, 8.3 Hz, 1H) ppm.

Example 76.4-(6-Methoxy-3-(6-(1-methyl-5-oxopyrrolidin-3-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile

This compound was prepared according to the procedures described inExample 75, using1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrrolidin-2-oneenantiomer peak 2 instead of peak 1 from step 3. The product wasisolated as the TFA salt.

The two enantiomers were separated with chiral prep-HPLC (Phenomenex LUXAmylose-1 Sum 21.2×250 mm, eluting with 45% EtOH in hexanes, at flowrate of 20 mL/min, t_(R, peak 1)=9.7 min, t_(R, peak 2)=12.7 min), inwhich peak 2 is the desired product. LCMS calculated for C₂₇H₂₅N₆O₂(M+H)⁺: m/z=465.2; Found: 465.2.

Example 77.(S)-1-(4-(5-(5-(2,3-Dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidin-1-yl)-2-hydroxypropan-1-one

Step 1.5-(2,3-Dimethylphenyl)-3-iodo-6-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine

To a DMF (10 mL) solution of5-(2,3-dimethylphenyl)-3-iodo-6-methoxy-1H-pyrazolo[4,3-b]pyridine (1.5g, 3.90 mmol) was added DIEA (1.363 ml, 7.80 mmol) and SEM-Cl (1.04 ml,5.85 mmol) at 0° C. After stirring overnight, the reaction was treatedwith water and the product was extracted with EtOAc. The combinedorganic phases were washed with sat. NaCl solution, dried over Na₂SO₄,filtered, concentrated to dryness and purified by flash columnchromatography to afford the desired product. LC-MS calculated forC₂₁H₂₉IN₃O₂Si (M+H)⁺: m/z=510.1; found 510.1.

Step 2.3-(6-Chloropyridin-3-yl)-5-(2,3-dimethylphenyl)-6-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine

To a solution of5-(2,3-dimethylphenyl)-3-iodo-6-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine(761 mg, 1.493 mmol) in 1,4-dioxane (5 mL) and water (1 mL) were added(6-chloropyridin-3-yl)boronic acid (282 mg, 1.792 mmol), K₃PO₄ (633 mg,2.99 mmol), and PdCl₂(dppf)-CH₂Cl₂ adduct (119 mg, 0.149 mmol). Thereaction was degassed with N₂ and stirred at 80° C. for 3 h. After thistime, it was cooled to r.t., diluted with EtOAc, washed sequentiallywith water, sat. NaCl and dried over Na₂SO₄. The organic phases werecombined, filtered, concentrated to dryness and purified by flash columnchromatography to afford the desired product. LC-MS calculated forC₂₆H₃₂ClN₄O₂Si (M+H)⁺: m/z=495.2; found 495.2.

Step 3. tert-butyl5-(5-(2,3-Dimethylphenyl)-6-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-3′,6′-dihydro-[2,4′-bipyridine]-1′(2′H)-carboxylate

To a solution of3-(6-chloropyridin-3-yl)-5-(2,3-dimethylphenyl)-6-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine(99 mg, 0.201 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) were addedtert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate(124 mg, 0.402 mmol), K₃PO₄ (85 mg, 0.402 mmol) andchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(16 mg, 0.02 mmol). The reaction was degassed with N₂ and stirred at100° C. for 3 h. After this time, it was cooled to r.t., diluted withEtOAc, washed sequentially with water, sat. NaCl and dried over Na₂SO₄.The organic phases were combined, filtered, concentrated to dryness andpurified by flash column chromatography to afford the desired product.LC-MS calculated for C₃₆H₄₈N₅O₄Si (M+H)⁺: m/z=642.3; found 642.2.

Step 4.5-(2,3-Dimethylphenyl)-6-methoxy-3-(6-(piperidin-4-yl)pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine

To a MeOH (5 mL) solution of tert-butyl5-(5-(2,3-dimethylphenyl)-6-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-3′,6′-dihydro-[2,4′-bipyridine]-1′(2′H)-carboxylate(100 mg, 0.156 mmol) was added Pd/C (16.58 mg, 0.016 mmol). The reactionwas purged with H₂ and stirred at r.t. connected to a balloon filledwith hydrogen for 4 hrs. After completion, the reaction was filtratedthrough a short Celite pipette and the reaction was concentrated. Thecrude product was dissolved in DCM (2 mL) and treated with TFA (0.5 mL)at r.t. The mixture was then concentrated to dryness and used in thenext reaction without further purification. LC-MS calculated forC₃₁H₄₂N₅O₂Si (M+H)⁺: m/z=544.3; found 544.2.

Step 5.(S)-1-(4-(5-(5-(2,3-Dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidin-1-yl)-2-hydroxypropan-1-one

To a THF (1 mL) solution of5-(2,3-dimethylphenyl)-6-methoxy-3-(6-(piperidin-4-yl)pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine(20 mg, 0.037 mmol) was added (S)-2-hydroxypropanoic acid (3.31 mg,0.037 mmol), DIEA (6.42 μl, 0.037 mmol) and HATU (13.98 mg, 0.037 mmol).After stirring overnight, 1 mL of 4 N HCl was added to the reaction,which was then heated to 50° C. for 30 min. MeOH was added and thereaction was purified by prep-LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min). The product was isolated as the TFA salt. LC-MS calculated forC₂₈H₃₂N₅O₃(M+H)⁺: m/z=486.2; found 486.2. ¹H NMR (400 MHz, DMSO-d6) δ13.41 (s, 1H), 9.49 (s, 1H), 8.67 (d, J=8.0 Hz, 1H), 7.57 (s, 1H), 7.49(d, J=8.2 Hz, 1H), 7.17 (m, 3H), 4.47 (m, 2H), 4.11 (d, J=13.4 Hz, 1H),3.86 (s, 3H), 3.14 (m, 1H), 3.08-3.00 (m, 1H), 2.72 (m, 1H), 2.32 (s,3H), 1.98 (s, 3H), 1.91 (d, J=12.5 Hz, 2H), 1.80-1.54 (m, 2H), 1.20 m,3H) ppm.

Example 78.1-(4-(5-(5-(2,3-Dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidin-1-yl)-2-hydroxyethan-1-one

This compound was prepared according to the procedure described inExample 77, using 2-hydroxyacetic acid instead of (S)-2-hydroxypropanoicacid. The product was isolated as the TFA salt. LC-MS calculated forC₂₇H₃₀N₅O₃(M+H)⁺: m/z=472.2; found 472.2. 1H NMR (600 MHz, DMSO-d6) δ13.77 (s, 1H), 9.67 (d, J=2.1 Hz, 1H), 9.07-8.97 (m, 1H), 7.84 (d, J=8.4Hz, 1H), 7.73 (s, 1H), 7.41-7.21 (m, 3H), 4.64 (d, J=12.8 Hz, 1H), 4.28(m, 1H), 3.99 (s, 3H), 3.98-3.92 (m, 2H), 3.29-3.20 (m, 2H), 2.87 (m,1H), 2.44 (s, 3H), 2.10 (s, 3H), 2.06 (d, J=13.1 Hz, 2H), 1.82 (m, 2H)ppm.

Example 79.4-(5-(5-(2,3-Dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclohexane-1-carboxylicacid

Step 1.5-(2,3-Dimethylphenyl)-3-iodo-6-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine

N-iodosuccinimide (0.586 g, 2.61 mmol) was added to a solution of5-(2,3-dimethylphenyl)-3-iodo-6-methoxy-1H-pyrazolo[4,3-b]pyridine (0.82g, 2.17 mmol) in DMF (6 ml) and the reaction was stirred at 60° C. for 1hr. After cooling with the ice bath, the mixture was treated with DIPEA(0.455 ml, 2.61 mmol), followed by SEM-Cl (0.385 ml, 2.17 mmol). Thereaction mixture was stirred at r.t. for 2 hrs, then treated with waterand the product was extracted with EtOAc. The organic phase was washedwith sat. Na₂S₂O₃, brine, dried over Na₂SO₄, filtered and concentrated.The residue was purified by Biotage Isolera to afford the desiredproduct. LC-MS calculated for C₂₁H₂₉IN₃O₂Si (M+H)⁺: m/z=510.1; found510.0.

Step 2.3-(6-Chloropyridin-3-yl)-5-(2,3-dimethylphenyl)-6-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine

5-(2,3-Dimethylphenyl)-3-iodo-6-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine(0.500 g, 0.981 mmol), (6-chloropyridin-3-yl)boronic acid (0.232 g,1.472 mmol), bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (75mg, 0.09 mmol) and K₃PO₄ (0.417 g, 1.96 mmol) were placed in a vial withseptum. The vial was evacuated and backfilled with N₂ three times,1,4-dioxane (5 mL) and water (0.5 mL) were added, and the reaction wasstirred at 60° C. for 1 hr. The mixture was filtered. The filtrate waspartitioned between water and EtOAc. The organic phase was separated,washed with brine, dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by Biotage Isolera to afford the desired product.LC-MS calculated for C₂₆H₃₂ClN₄O₂Si (M+H)⁺: m/z=495.2; found 495.3.

Step 3. Ethyl4-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclohex-3-ene-1-carboxylate

3-(6-Chloropyridin-3-yl)-5-(2,3-dimethylphenyl)-6-methoxy-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-pyrazolo[4,3-b]pyridine(430 mg, 0.869 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate(365 mg, 1.3 mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(68 mg, 0.087 mmol) and K₃PO₄ (221 mg, 1.042 mmol) were placed in a vialwith septum. The vial was evacuated and backfilled with N₂ three times,1,4-dioxane (5 mL) and water (1.0 mL) were added and the reactionmixture was stirred at 80° C. for 7 hrs. After cooling to r.t., thereaction was treated with water and the product was extracted withEtOAc. The organic phase was separated, washed with brine, dried andconcentrated. The residue was purified by Biotage Isolera to afford thedesired product. LC-MS calculated for C₃₅H₄₅N₄O₄Si (M+H)⁺: m/z=613.3;found 613.5.

Step 4.4-(5-(5-(2,3-Dimethylphenyl)-6-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclohexane-1-carboxylicacid

A mixture of ethyl4-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclohexane-1-carboxylate(0.53 g, 0.865 mmol) and platinum(IV) oxide hydrate (0.068 g, 0.259mmol) in ethyl acetate (10 ml) was stirred under a balloon of hydrogenat r.t. overnight. The reaction was then filtered through a pad ofCelite and rinsed with EtOAc. After concentrating in vacuo, the residuewas purified by Biotage Isolera to afford the ester intermediate. Theester was dissolved in a THF (2 ml), MeOH (2 ml), and water (2 ml)mixture. 1M solution of sodium hydroxide (4.32 ml, 4.32 mmol) was addedto the resulted solution. The reaction mixture was stirred at r.t. for 1h. The organic solvents were removed in vacuo, and pH of the resultingsolution was adjusted to 4-5 with 1N HCl solution. The solids formedwere collected by filtration, washed with water, and air dried to givethe desired product. LC-MS calculated for C₃₃H₄₃N₄O₄Si (M+H)⁺:m/z=587.3; found 587.4.

Step 5.4-(5-(5-(2,3-Dimethylphenyl)-6-methoxy-M-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclohexane-1-carboxylicacid

TFA (0.5 ml, 2.60 mmol) was added to a solution of4-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclohexane-1-carboxylicacid (20 mg, 0.034 mmol) in DCM (0.5 ml) and the reaction mixture wasstirred at r.t. for 1 h. After concentrating in vacuo, the residue wastreated with ammonium hydroxide solution in water (28%) (0.5 ml) andMeOH (1 ml). The reaction mixture was stirred at r.t. for 1 h. Thereaction was then diluted with water and MeOH and purified by prep-LCMS(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% TFA, at flow rate of 60 mL/min). The product wasisolated as the TFA salt. LCMS calculated for C₂₇H₂₉N₄O₃ (M+H)⁺:m/z=457.2; found 457.2.

Example 80.(3S,4R)-1-(5-(5-(2,3-Dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-4-fluoropyrrolidin-3-amine

Step 1.5-(2,3-Dimethylphenyl)-3-(6-fluoropyridin-3-yl)-6-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine

5-(2,3-Dimethylphenyl)-3-iodo-6-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine(0.830 g, 1.629 mmol), (6-fluoropyridin-3-yl)boronic acid (0.344 g,2.444 mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(0.128 g, 0.163 mmol) and K₃PO₄ (0.69 g, 3.26 mmol) were placed in avial with septum. The vial was evacuated and backfilled with N₂ threetimes, 1,4-dioxane (10 mL) and water (2 mL) were added, and the reactionmixture was stirred at 60° C. for 1 h. The mixture was filtered. Thefiltrate was partitioned between water and EtOAc. The organic phase wasseparated, washed with brine, dried over Na₂SO₄, filtered andconcentrated. The residue was purified by Biotage Isolera to afford thedesired product. LC-MS calculated for C₂₆H₃₂FN₄O₂Si (M+H)⁺: m/z=479.2;found 479.1.

Step 2.(3S,4R)-1-(5-(5-(2,3-Dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-4-fluoropyrrolidin-3-amine

A mixture of5-(2,3-dimethylphenyl)-3-(6-fluoropyridin-3-yl)-6-methoxy-1-((2-(trimethylsilyl)-ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine(20 mg, 0.042 mmol), tert-butyl((3S,4R)-4-fluoropyrrolidin-3-yl)carbamate (8.53 mg, 0.042 mmol) andDIPEA (21.89 μl, 0.125 mmol) in DMSO (0.2 ml) was stirred at 110° C.overnight. After cooling to r.t., the mixture was partitioned betweenwater and EtOAc. The organic phase was separated, washed with brine,dried and concentrated. The residue was dissolved in DCM (0.5 ml),treated with TFA (0.5 ml, 2.60 mmol) and stirred at r.t. for 1 h. Afterconcentrating in vacuo, the residue was treated with ammonium hydroxidesolution in water (28%) (0.5 ml) and MeOH (1 ml). The reaction mixturewas stirred at r.t for 1 h. The reaction was then diluted with water andMeOH and purified by prep-LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min). The product was isolated as the TFA salt. LCMS calculated forC₂₄H₂₆FN₆O (M+H)⁺: m/z=433.2; found 433.2. ¹H NMR (600 MHz, DMSO-d6) δ9.18 (s, 1H), 8.66 (s, 2H), 8.53 (dd, J=8.9, 2.3 Hz, 1H), 7.53 (s, 1H),7.25-7.21 (m, 1H), 7.17 (t, J=7.5 Hz, 1H), 7.12 (d, J=9.0 Hz, 1H), 6.80(d, J=9.0 Hz, 1H), 5.50 (dt, J=53.9, 3.5 Hz, 1H), 4.25-4.08 (m, 1H),4.05-3.98 (m, 1H), 3.95-3.86 (m, 1H), 3.85 (s, 3H), 3.78 (dd, J=13.2,3.5 Hz, 1H), 3.48 (t, J=9.7 Hz, 1H), 2.32 (s, 3H), 1.98 (s, 3H) ppm.

Example 81.(2S)-1-(4-(5-(5-(2-Fluoro-2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidin-1-yl)-2-hydroxypropan-1-one

Step 1. Chiral Separation of 4-bromo-2,3-dihydro-1H-inden-2-ol

Two enantiomers of the commercially available4-bromo-2,3-dihydro-1H-inden-2-ol were separated by chiral prep-SFC(ChiralTech IG Sum 21×250 mm, eluting with 15% EtOH (containing 2 mMammonia), at flow rate of 70 mL/min, t_(R, peak 1)=3.2 min,t_(R, peak 2)=3.9 min). Peak 2 was collected and the solvents wereevaporated in vacuo.

Step 2. 4-Bromo-2-fluoro-2,3-dihydro-1H-indene

A solution of 4-bromo-2,3-dihydro-1H-inden-2-ol (0.50 g, 2.3 mmol) (Peak2 from chiral separation in Step 1) in DCM (5 mL) was cooled in dryice/acetone bath before DAST (0.4 mL, 3.03 mmol) was slowly added. After30 min the mixture was allowed to warm to r.t. The reaction was treatedwith ice and the product was extracted with DCM. The organic phase wasseparated, washed with brine, dried over sodium sulfate and the solventwas removed in vacuo. The obtained crude material was purified byBiotage Isolera.

Step 3.2-(2-Fluoro-2,3-dihydro-1H-inden-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

A mixture of 4-bromo-2-fluoro-2,3-dihydro-1H-indene (0.20 g, 0.930mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(0.472 g, 1.9 mmol),[1,1′-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II) (25 mg,0.03 mmol) and potassium acetate (0.5 g) in dioxane (5 mL) was stirredat 80° C. overnight. After cooling to r.t., the reaction mixture wasfiltered, the solvent was evaporated in vacuo and the crude material waspurified by Biotage Isolera.

Step 4.5-(2-Fluoro-2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine

A mixture of2-(2-fluoro-2,3-dihydro-1H-inden-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(0.25 g, 0.95 mmol), tert-butyl5-chloro-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate (0.27 g,0.954 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(25 mg, 33 mmol) and K₃PO₄ (300 mg) in dioxane (4 mL) and water (0.4 mL)was stirred at 80° C. under nitrogen overnight. After cooling to r.t.,the reaction mixture was filtered, the solvent was evaporated in vacuoand the crude material was purified by Biotage Isolera.

4N HCl in dioxane (2 mL) was then added to the desired product and thereaction mixture was stirred at r.t. for 2 hrs. It was diluted withethyl acetate and neutralized with NaHCO₃ solution. The organic phasewas separated, washed with brine, dried over sodium sulfate, filteredand the solvents were removed in vacuo. LC-MS calculated for C₁₆H₁₅FN₃O(M+H)⁺: m/z=284.1; found 284.2.

Step 5. tert-Butyl5-(2-fluoro-2,3-dihydro-1H-inden-4-yl)-3-iodo-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate

NIS (0.206 g, 0.918 mmol) was added to a solution of5-(2-fluoro-2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine(0.26 g, 0.918 mmol) in DMF (5 ml). After stirring at 60° C. for 2 h,the reaction mixture was cooled to r.t., and triethylamine (0.23 ml,1.64 mmol) and Boc-anhydride (0.30 g, 1.37 mmol) were added. Afteradditional stirring at r.t. for 1 h, water was added and precipitatedproduct was collected by filtration, air dried and used in the next stepwithout further purification. LC-MS calculated for C₂₁H₂₂FIN₃O₃ (M+H)⁺:m/z=510.1; found 510.1.

Step 6. tert-Butyl5-bromo-3′,6′-dihydro-[2,4′-bipyridine]-1′(2′H)-carboxylate

A mixture of tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate(1.85 g, 5.98 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(250 mg, 0.330 mmol), K₃PO₄ (1.0 g) in dioxane (10 mL) and water (2 mL)was stirred at 80° C. overnight. The reaction mixture was then cooled tor.t., filtered, and the solvent was evaporated in vacuo. The obtainedcrude material was purified by Biotage Isolera twice to give 0.23 g ofwhite solid. LC-MS calculated for C₁₁H₁₁BrN₂O₂ (M-tBu+H)⁺: m/z=282.1,284.1; found 282.1, 284.1.

Step 7. tert-Butyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3′,6′-dihydro-[2,4′-bipyridine]-1′(2′H)-carboxylate

A mixture of 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(0.275 g, 1.085 mmol), tert-butyl5-bromo-3′,6′-dihydro-[2,4′-bipyridine]-1′(2′H)-carboxylate (0.23 g,0.678 mmol), potassium acetate (0.2 g) and[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (50 mg,0.06 mmol) in dioxane (3 mL) was stirred at 80° C. overnight. Aftercooling to r.t., the reaction mixture was filtered, the solvent wasevaporated in vacuo and the crude material was purified by BiotageIsolera. LC-MS calculated for C₂₁H₃₂BN₂O₄ (M+H)⁺: m/z=387.2; found387.2.

Step 8. tert-Butyl3-(1′-(tert-butoxycarbonyl)-1′,2′,3′,6′-tetrahydro-[2,4′-bipyridin]-5-yl)-5-(2-fluoro-2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate

A mixture of tert-butyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3′,6′-dihydro-[2,4′-bipyridine]-1′(2′H)-carboxylate(0.050 g, 0.130 mmol), tert-butyl5-(2-fluoro-2,3-dihydro-1H-inden-4-yl)-3-iodo-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate(0.066 g, 0.130 mmol)chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(8 mg, 11 μmol) and K₃PO₄ (0.050 g) in dioxane (3 mL) and water (0.3 mL)was stirred at 80° C. overnight. After cooling to r.t., the reactionmixture was filtered and the solvent was evaporated in vacuo. The crudematerial was dissolved in methanol and purified by prep-LCMS (XBridgeC18 column, eluting with a gradient of acetonitrile/water containing0.1% TFA, at flow rate of 60 mL/min). LC-MS calculated for C₃₆H₄₁FN₅O₅(M+H)⁺: m/z=642.3, found 642.3.

Step 9.5-(2-Fluoro-2,3-dihydro-1H-inden-4-yl)-6-methoxy-3-(6-(piperidin-4-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine

A mixture of tert-butyl3-(1′-(tert-butoxycarbonyl)-1′,2′,3′,6′-tetrahydro-[2,4′-bipyridin]-5-yl)-5-(2-fluoro-2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate(0.010 g, 0.016 mmol) and palladium on carbon (5 mg, 10%) in methanol (5mL) was connected to a balloon filled with hydrogen and the reactionmixture was stirred at r.t. for 3 hrs. The reaction mixture was thenfiltered and concentrated in vacuo. 4N HCl solution in dioxane was thenadded and the reaction was stirred at r.t. for 30 min. It was thendiluted with methanol and purified by prep-LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min). LC-MS calculated for C₂₆H₂₇FN₅O (M+H)⁺:m/z=444.1, found 444.1.

Step 10.(2S)-1-(4-(5-(5-(2-Fluoro-2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidin-1-yl)-2-hydroxypropan-1-one

HATU (35 mg, 0.09 mmol) was added to a solution of(S)-2-hydroxypropanoic acid (32 mg, 0.355 mmol),5-(2-fluoro-2,3-dihydro-1H-inden-4-yl)-6-methoxy-3-(6-(piperidin-4-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine(5 mg, 10.15 μmol) and DIPEA (0.05 mL) in DMF (1 mL). After stirring atr.t. for 1 h, the reaction mixture was diluted with methanol, filteredand purified with prep-LCMS (XBridge C18 column, eluting with a gradientof acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min).The product was isolated as the TFA salt. LC-MS calculated forC₂₉H₃₁FN₅O₃ (M+H)⁺: m/z=516.3, found 516.3.

Example 82.1-(4-(5-(5-(2-Fluoro-2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidin-1-yl)-2-hydroxyethan-1-one

This compound was prepared according to the procedures described inExample 81, using 2-hydroxyacetic acid instead of (S)-2-hydroxypropanoicacid as starting material. The product was isolated as the TFA salt.LC-MS calculated for C₂₈H₂₉FN₅O₃ (M+H)⁺: m/z=502.2, found 502.2.

Example 83.(7R,8aS)-2-(5-(5-(2-Fluoro-2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol

Step 1.(7R,8aS)-2-(5-Bromopyridin-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-01

A mixture of (7R,8aS)-octahydropyrrolo[1,2-c]pyrazin-7-ol (0.045 g,0.316 mmol), 5-bromo-2-fluoropyridine (0.056 g, 0.316 mmol) and Cs₂CO₃(120 mg, 0.369 mmol) in DMF (1 mL) was stirred at 80° C. for 4 h. Thesolvent was then evaporated in vacuo and the residue was purified byBiotage Isolera. LC-MS calculated for C₁₂H₁₇BrN₃O (M+H)⁺: m/z=298.1,300.1, found 297.9, 299.9.

Step 2.(7R,8aS)-2-(5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol

A mixture of 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(0.061 g, 0.241 mmol),(7R,8aS)-2-(5-bromopyridin-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol(0.045 g, 0.151 mmol), potassium acetate (0.050 g) and[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (16 mg,0.02 mmol) in dioxane (2 mL) was stirred at 80° C. overnight. Aftercooling to r.t., the reaction mixture was filtered, the solvent wasevaporated in vacuo and the crude material was purified by prep-LCMS(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% TFA, at flow rate of 60 mL/min). LC-MS calculated forC₁₈H₂₉BN₃O₃ (M+H)⁺: m/z=346.2, found 346.2.

Step 3.(7R,8aS)-2-(5-(5-(2-Fluoro-2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-01

A mixture of(7R,8aS)-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)octahydropyrrolo[1,2-c]pyrazin-7-ol(0.027 g, 0.079 mmol), tert-butyl5-(2-fluoro-2,3-dihydro-1H-inden-4-yl)-3-iodo-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate(0.020 g, 0.039 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(8 mg, 10 μmol) and K₃PO₄ (10 mg) in dioxane (1 mL) and water (0.1 mL)was stirred at 80° C. overnight. The mixture was concentrated in vacuo.After methanol (1 mL) and 4N HCl in dioxane (1 mL) were added, theobtained reaction mixture was stirred at r.t. for 1 h. It was thendiluted with methanol, filtered and purified by prep-LCMS (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%TFA, at flow rate of 60 mL/min). The product was isolated as the TFAsalt. LC-MS calculated for C₂₈H₃₀FN₆O₂ (M+H)⁺: m/z=501.3, found 501.2.¹H NMR (500 MHz, DMSO-d₆) δ 9.30-9.19 (m, 1H), 8.52 (dd, J=8.8, 2.3 Hz,1H), 7.55 (s, 1H), 7.43-7.35 (m, 2H), 7.32 (t, J=7.5 Hz, 1H), 6.91 (d,J=8.9 Hz, 1H), 5.49 (dt, J=53.5, 4.8 Hz, 1H), 4.71 (dd, J=102.1, 13.9Hz, 1H), 4.47 (d, J=4.0 Hz, 1H), 4.30 (dd, J=14.5, 4.5 Hz, 1H),4.18-4.04 (m, 1H), 3.90 (s, 3H), 3.85-3.75 (m, 1H), 3.73-3.59 (m, 2H),3.56-3.11 (m, 6H), 2.96 (dd, J=25.8, 17.8 Hz, 1H), 2.15-1.94 (m, 2H)ppm.

Example 84.5-(2-Fluoro-2,3-dihydro-1H-inden-4-yl)-6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine

This compound was prepared according to the procedures described inExample 83, using1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleinstead of(7R,8aS)-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)octahydropyrrolo[1,2-c]pyrazin-7-olas starting material. The product was isolated as the TFA salt. LC-MScalculated for C₂₀H₁₉FN₅O (M+H)⁺: m/z=364.1, found 364.1. ¹H NMR (600MHz, DMSO-d6) δ 8.29 (s, 1H), 8.06 (s, 1H), 7.49 (s, 1H), 7.40 (d, J=7.6Hz, 1H), 7.38-7.34 (m, 1H), 7.33-7.29 (m, 1H), 5.62-5.36 (m, 1H), 3.91(s, 3H), 3.89 (s, 3H), 3.45-3.13 (m, 3H), 3.01 (dd, J=25.9, 17.8 Hz, 1H)ppm.

Example 85.(7S,8aR)-2-(5-(5-(2,3-Dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol

Step 1. tert-Butyl5-(2,3-dimethylphenyl)-3-(6-fluoropyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate

A mixture of tert-butyl5-(2,3-dimethylphenyl)-3-iodo-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate(200 mg, 0.417 mmol),2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (186mg, 0.835 mmol), XphosPd G2 (32.8 mg, 0.042 mmol), and potassiumphosphate (354 mg, 1.669 mmol) in dioxane (5 ml) and water (0.5 ml) washeated to 80° C. for 2 hrs. After this time the solution was cooled tor.t., diluted with water and extracted with EtOAc. The combined organicphases were washed with sat. aq. NaCl and dried over Na₂SO₄, thenfiltered and concentrated to dryness. The residue was purified byBiotage Isolera to afford the desired product. LCMS calculated forC₂₅H₂₆FN₄O₃ (M+H)⁺: m/z=449.2; found 449.2.

Step 2.(7S,8aR)-2-(5-(5-(2,3-Dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol

A solution of tert-butyl5-(2,3-dimethylphenyl)-3-(6-fluoropyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate(20 mg, 0.045 mmol), (7S,8aR)-octahydropyrrolo[1,2-a]pyrazin-7-oldihydrochloride (28.8 mg, 0.134 mmol), and N,N-diisopropylethylamine (78μl, 0.45 mmol) in DMSO (1 ml) was heated at 100° C. for 20 hrs. Afterthis time the solution was cooled to r.t., diluted with water andextracted with EtOAc. The combined organic phases were washed with sat.aq. NaCl and dried over Na₂SO₄, then filtered and concentrated todryness. The residue was then dissolved in DCM (1 mL) and TFA (1 mL) wasadded. The mixture was stirred at r.t. for 1 hr and purified byprep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). Theproduct was isolated as the TFA salt. LCMS calculated for C₂₇H₃₁N₆O₂(M+H)⁺: m/z=471.2; found 471.5.

Example 86.4-(5-(5-(2,3-Dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-1-imino-1λ⁶-thiomorpholine1-oxide

This compound was prepared according to the procedure described inExample 85, using 1-imino-1κ⁶-thiomorpholine 1-oxide hydrochlorideinstead of (7S,8aR)-octahydropyrrolo[1,2-c]pyrazin-7-ol dihydrochlorideas starting material. The product was isolated as the TFA salt. LC-MScalculated for C₂₄H₂₇N₆O₂S (M+H)⁺: m/z=463.2; found 463.2. ¹H NMR (500MHz, DMSO-d6) δ 9.23 (d, J=2.3 Hz, 1H), 8.52 (dd, J=8.9, 2.3 Hz, 1H),7.52 (s, 1H), 7.25-7.14 (m, 3H), 7.11 (dd, J=7.6, 1.5 Hz, 1H), 4.59 (dt,J=15.1, 4.1 Hz, 2H), 3.85 (s, 3H), 3.81-3.72 (m, 2H), 3.72-3.64 (m, 2H),3.60-3.52 (m, 2H), 2.32 (s, 3H), 1.98 (s, 3H) ppm.

Example 87.(7R,8aS)-2-(5-(5-(2,3-Dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol

Step 1. tert-Butyl5-(2,3-dimethylphenyl)-3-(6-fluoropyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate

A mixture of tert-butyl5-(2,3-dimethylphenyl)-3-iodo-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate(200 mg, 0.417 mmol) (Example 41, Step 7),2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (186mg, 0.835 mmol), XphosPd G2 (32.8 mg, 0.042 mmol), and potassiumphosphate (354 mg, 1.669 mmol) in dioxane (5 ml) and water (0.5 ml) washeated to 80° C. for 2 hrs. After this time the solution was cooled tor.t., diluted with water and extracted with EtOAc. The combined organicphases were washed with sat. aq. NaCl and dried over Na₂SO₄, thenfiltered and concentrated to dryness. The residue was then purified bysilica gel chromatography to afford the desired product. LCMS calculatedfor C₂₅H₂₆FN₄O₃ (M+H)⁺: m/z=449.2; found 449.2.

Step 2.(7R,8aS)-2-(5-(5-(2,3-Dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol

A solution of tert-butyl5-(2,3-dimethylphenyl)-3-(6-fluoropyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate(20 mg, 0.045 mmol), (7R,8aS)-octahydropyrrolo[1,2-c]pyrazin-7-ol (19.0mg, 0.134 mmol), and N,N-diisopropylethylamine (38.9 μl, 0.223 mmol) inDMSO (1 ml) was heated at 100° C. for 20 hrs. After this time thesolution was cooled to r.t., diluted with water and extracted withEtOAc. The combined organic phases were washed with sat. aq. NaCl anddried over Na₂SO₄, then filtered and concentrated to dryness. Theresidue was then dissolved in DCM (1 mL) and TFA (1 mL) was added. Themixture was stirred at r.t. for 1 hr and purified by prep-LCMS (XBridgeC18 column, eluting with a gradient of acetonitrile/water containing0.1% TFA, at flow rate of 60 mL/min). The product was isolated as theTFA salt. LCMS calculated for C₂₇H₃₁N₆O₂ (M+H)⁺: m/z=471.2; found 471.5.¹H NMR (500 MHz, DMSO-d6, for the free base version) δ 9.15 (d, J=2.3Hz, 1H), 8.41 (dd, J=9.1, 2.4 Hz, 1H), 7.54 (s, 1H), 7.22 (d, J=7.4 Hz,1H), 7.16 (t, J=7.5 Hz, 1H), 7.11 (d, J=7.5 Hz, 1H), 6.94 (d, J=9.0 Hz,1H), 4.46-4.35 (m, 1H), 4.29-4.20 (m, 2H), 3.83 (s, 3H), 3.45-3.18 (m,2H), 3.00-2.92 (m, 1H), 2.84 (td, J=12.2, 3.4 Hz, 1H), 2.47 (t, J=11.1Hz, 1H), 2.32 (s, 3H), 2.30-2.14 (m, 2H), 1.99-1.94 (m, 4H), 1.69-1.58(m, 2H).

Example 88.(S)—N-(1-(5-(5-(2,3-Dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)pyrrolidin-3-yl)-2-hydroxy-N-methylacetamide

Step 1. tert-Butyl(5)-methyl(1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrrolidin-3-yl)carbamate

This compound was prepared according to the procedure described inExample 83, Step 1-2, using tert-butyl(S)-methyl(pyrrolidin-3-yl)carbamate instead of(7R,8aS)-octahydropyrrolo[1,2-a]pyrazin-7-ol as starting material. LC-MScalculated for C₂₁H₃₅BN₃O₄ (M+H)⁺: m/z=404.3, found 404.2.

Step 2.(S)-1-(5-(5-(2,3-Dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-N-methylpyrrolidin-3-amine

A mixture of tert-butyl5-(2,3-dimethylphenyl)-3-iodo-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate(0.20 g, 0.42 mmol), tert-butyl(S)-methyl(1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrrolidin-3-yl)carbamate(0.26 g, 0.81 mmol), XPhosPd G2 (20 mg, 25 μmol) and K₃PO₄ (0.050 g,0.24 mmol) in dioxane (5 mL) water (0.5 mL) was stirred at 80° C.overnight. After cooling to r.t., the reaction was filtered, the solventevaporated in vacuo and the residue was purified by Biotage Isolera. Thefractions containing the desired product were combined and concentratedin vacuo. 4N HCl in dioxane (2 mL) was added to the obtained materialand the reaction mixture was stirred at r.t. for 1 hr. It was thenconcentrated in vacuo and was directly used in the next step withoutfurther purification. LC-MS calculated for C₂₅H₂₉N₆O (M+H)⁺: m/z=429.2,found 429.1.

Step 3.(S)—N-(1-(5-(5-(2,3-Dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)pyrrolidin-3-yl)-2-hydroxy-N-methylacetamide

HATU (100 mg, 0.263 mmol) was added to a solution of(S)-1-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-N-methylpyrrolidin-3-amine(0.078 g, 0.18 mmol), 2-hydroxyacetic acid (0.100 g, 1.32 mmol) andDIPEA (0.05 mL, 0.29 mmol) in DMF (2 mL). After stirring at r.t. for 1hr, the reaction mixture was diluted with methanol, filtered andpurified by prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). Theproduct was isolated as the TFA salt. LC-MS calculated for C₂₇H₃₁N₆O₃(M+H)⁺: m/z=487.3, found 487.2.

Example 89.2-(3-(3-(6-(4-(2-Hydroxyethyl)piperazin-1-yl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2-methylphenyl)acetonitrile

Step 1.2-(4-(5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazin-1-yl)ethan-1-01

To a solution of1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine(25 mg, 0.086 mmol) and cesium carbonate (85 mg, 0.26 mmol) in1,4-dioxane (0.62 mL) was added 2-bromoethan-1-ol (12 μL, 0.18 mmol).The reaction was stirred at 50° C. for 3 hrs. After cooling to r.t., thereaction mixture was filtered, the solvent evaporated in vacuo and crudematerial was used in next step without further purification. LCMScalculated for C₁₁H₁₉BN₃O₃ (Boronic acid, M+H)⁺: m/z=252.2, found:252.3.

Step 2.2-(3-(3-(6-(4-(2-Hydroxyethyl)piperazin-1-yl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2-methylphenyl)acetonitrile

To a solution of tert-butyl5-(3-(cyanomethyl)-2-methylphenyl)-3-iodo-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate(Example 55, step 1; 30 mg, 0.059 mmol) in 1,4-dioxane (0.27 mL) andwater (27 μL) was added2-(4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazin-1-yl)ethan-1-ol(25 mg, 0.074 mmol), potassium phosphate (19 mg, 0.089 mmol), andXphosPd G2 (9 mg, 0.01 mmol). The reaction was degassed with N₂ andstirred at 80° C. for 1 hr. After this time it was cooled to r.t., and 1mL of TFA was added. The reaction was stirred for additional 30 minbefore it was diluted with MeOH and purified by prep-LCMS (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%TFA, at flow rate of 60 mL/min followed by a second C18 column, elutingwith a gradient of acetonitrile/water containing 0.15% NH₄OH, at flowrate of 60 mL/min). The product was isolated as the TFA salt. LC-MScalculated for C₂₇H₃₀N₇O₂ (M+H)⁺: m/z=484.3, found 484.4. ¹H NMR (600MHz, DMSO-d6) δ 13.30-13.10 (s, 1H), 9.74-9.64 (s, 1H), 9.19 (d, J=2.3Hz, 1H), 8.47 (dd, J=8.9, 2.3 Hz, 1H), 7.54 (s, 1H), 7.44 (dd, J=7.6,1.4 Hz, 1H), 7.33 (t, J=7.6 Hz, 1H), 7.28 (dd, J=7.7, 1.5 Hz, 1H), 7.08(d, J=8.9 Hz, 1H), 4.42 (d, J=13.9 Hz, 2H), 4.09 (s, 2H), 3.84 (s, 3H),3.76 (dd, J=6.1, 4.3 Hz, 2H), 3.58 (d, J=12.1 Hz, 2H), 3.33-3.18 (m,4H), 3.17-3.08 (m, 2H), 2.05 (s, 3H) ppm.

Example 90.(7R,8aS)-2-(5-(6-Methoxy-5-(3-methoxy-2-methylphenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol

Step 1. tert-Butyl5-chloro-3-(6-((7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate

This compound was prepared according to the procedures described inExample 1, Steps 1-7, using(7R,8aS)-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)octahydropyrrolo[1,2-c]pyrazin-7-ol(Example 83, Steps 1-2) instead of1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole asstarting material. LCMS calculated for C₂₄H₃₀ClN₆O₄ (M+H)⁺: m/z=501.2,found: 501.2.

Step 2.(7R,8aS)-2-(5-(6-Methoxy-5-(3-methoxy-2-methylphenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol

tert-Butyl5-chloro-3-(6-((7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate(8 mg, 0.02 mmol), (3-methoxy-2-methylphenyl)boronic acid (5.30 mg,0.032 mmol), XphosPd G2 (1.9 mg, 2.4 μmol) and potassium phosphate (5.1mg, 0.024 mmol) were placed in a vial and the vial was evacuated andbackfilled with N₂ three times. After 1,4-dioxane (1 ml) and water (100μl) were added, the reaction mixture was stirred at 100° C. for 1 hr.Then the reaction was filtered, and the solvents were evaporated invacuo. DCM (1 ml) and TFA (0.5 ml) were added and the reaction mixturewas stirred at r.t. for 30 min. It was then diluted with CH₃CN and waterand purified with prep-LCMS (XBridge C18 column, eluting with a gradientof acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min).The product was isolated as the TFA salt. LCMS calculated for C₂₇H₃₁N₆O₃(M+H)⁺: m/z=487.3, found: 487.3. ¹H NMR (500 MHz, DMSO-d6) δ 9.23-9.16(m, 1H), 8.51 (dd, J=8.9, 2.3 Hz, 1H), 7.52 (s, 1H), 7.25 (t, J=7.9 Hz,1H), 7.03 (dd, J=8.4, 1.2 Hz, 1H), 6.94 (d, J=9.0 Hz, 1H), 6.90 (dd,J=7.6, 1.1 Hz, 1H), 4.52-4.43 (m, 1H), 4.35-4.23 (m, 1H), 4.16-4.00 (m,1H), 3.89-3.83 (m, 6H), 3.82-3.75 (m, 1H), 3.73-3.60 (m, 3H), 3.56-3.47(m, 1H), 3.47-3.40 (m, 2H), 2.19-1.95 (m, 2H), 1.92 (s, 3H) ppm.

Example 91.(7R,8aS)-2-(5-(5-(2,3-Dihydrobenzo[b][1,4]dioxin-5-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol

This compound was prepared according to the procedures described inExample 90, using2-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneinstead of (3-methoxy-2-methylphenyl)boronic acid as starting material.The product was isolated as the TFA salt. LCMS calculated for C₂₇H₂₉N₆O₄(M+H)⁺: m/z=501.2; Found: 501.2.

Example 92.(7R,8aS)-2-(5-(5-(2-Cyclopropylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol

This compound was prepared according to the procedures described inExample 90, using (2-cyclopropylphenyl)boronic acid instead of(3-methoxy-2-methylphenyl)boronic acid as starting material. The productwas isolated as the TFA salt. LCMS calculated for C₂₈H₃₁N₆O₂ (M+H)⁺:m/z=483.2; Found: 483.3.

Example 93.(7R,8aS)-2-(5-(5-(Chroman-5-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol

This compound was prepared according to the procedures described inExample 90, using2-(chroman-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane acid instead of(3-methoxy-2-methylphenyl)boronic acid as starting material. The productwas isolated as the TFA salt. LCMS calculated for C₂₈H₃₁N₆O₃ (M+H)⁺:m/z=499.3; Found: 499.2.

Example 94.(7R,8aS)-2-(5-(5-(2-Fluoro-3-methylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol

This compound was prepared according to the procedures described inExample 90, using (2-fluoro-3-methylphenyl)boronic acid instead of(3-methoxy-2-methylphenyl)boronic acid as starting material. The productwas isolated as the TFA salt. LCMS calculated for C₂₆H₂₈FN₆O₂ (M+H)⁺:m/z=475.2; Found: 475.2. ¹H NMR (500 MHz, DMSO-d₆) δ 9.25-9.18 (m, 1H),8.50 (dd, J=8.9, 2.3 Hz, 1H), 7.55 (s, 1H), 7.37 (t, J=7.4 Hz, 1H),7.35-7.31 (m, 1H), 7.21 (t, J=7.5 Hz, 1H), 6.94 (d, J=9.0 Hz, 1H), 4.47(s, 1H), 4.30 (dd, J=14.0, 4.3 Hz, 1H), 4.16-4.06 (m, 1H), 3.88 (s, 3H),3.84-3.76 (m, 1H), 3.73-3.60 (m, 3H), 3.58-3.46 (m, 1H), 3.46-3.39 (m,2H), 2.31 (s, 3H), 2.17-1.91 (m, 2H) ppm.

Example 95.4-(6-Methoxy-3-(6-(2-methoxyethoxy)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-2-ol

Step 1.2-(2-Methoxyethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

A mixture of 5-bromo-2-(2-methoxyethoxy)pyridine (250 mg, 1.08 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (356 mg, 1.4mmol), [1,1′-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II) (88mg, 0.11 mmol) and potassium acetate (159 mg, 1.62 mmol) in dioxane (5mL) was stirred at 80° C. overnight. After cooling to r.t., the reactionmixture was filtered, the solvent was evaporated in vacuo and the crudematerial was purified by Biotage Isolera. LCMS calculated for C₁₄H₂₃BNO₄(M+H)⁺: m/z=280.2; Found: 280.2.

Step 2.4-(6-Methoxy-3-(6-(2-methoxyethoxy)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-2-ol

This compound was prepared according to the procedures described inExample 73, using2-(2-methoxyethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridineinstead of2-((tetrahydrofuran-3-yl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridineas starting material. The product was isolated as the TFA salt. LCMScalculated for C₂₄H₂₅N₄O₄ (M+H)⁺: m/z=433.2; Found: 433.2. ¹H NMR (600MHz, DMSO-d₆) δ 9.23 (d, J=2.3 Hz, 1H), 8.62 (dd, J=8.6, 2.3 Hz, 1H),7.55 (s, 1H), 7.32 (d, J=7.3 Hz, 1H), 7.28 (d, J=6.1 Hz, 1H), 7.25 (t,J=7.4 Hz, 1H), 6.97 (d, J=8.7 Hz, 1H), 4.52-4.45 (m, 1H), 4.45-4.41 (m,2H), 3.89 (s, 3H), 3.71-3.64 (m, 2H), 3.31 (s, 3H), 3.16 (dd, J=16.0,6.0 Hz, 1H), 3.03 (dd, J=16.4, 6.0 Hz, 1H), 2.84 (dd, J=15.9, 3.8 Hz,1H), 2.65 (dd, J=16.4, 3.9 Hz, 1H) ppm.

Example 96.4-(6-Methoxy-3-(6-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-2-ol

This compound was prepared according to the procedures described inExample 95, using 5-bromo-2-((tetrahydro-2H-pyran-4-yl)oxy)pyridineinstead of 5-bromo-2-(2-methoxyethoxy)pyridine as starting material. Theproduct was isolated as the TFA salt. LCMS calculated for C₂₆H₂₇N₄O₄(M+H)⁺: m/z=459.2; Found: 459.2. ¹H NMR (600 MHz, DMSO-d6) δ 9.22 (d,J=2.4 Hz, 1H), 8.61 (dd, J=8.6, 2.3 Hz, 1H), 7.55 (s, 1H), 7.32 (d,J=5.9 Hz, 1H), 7.28 (d, J=6.1 Hz, 1H), 7.25 (t, J=7.4 Hz, 1H), 6.94 (d,J=8.6 Hz, 1H), 5.24 (tt, J=8.9, 4.2 Hz, 1H), 4.53-4.43 (m, 1H), 3.89 (s,3H), 3.88-3.83 (m, 2H), 3.57-3.45 (m, 2H), 3.16 (dd, J=16.0, 6.1 Hz,1H), 3.01 (dd, J=16.4, 6.0 Hz, 1H), 2.84 (dd, J=15.9, 3.8 Hz, 1H), 2.64(dd, J=16.4, 3.8 Hz, 1H), 2.09-2.01 (m, 2H), 1.75-1.60 (m, 2H) ppm.

Example 97.4-(3-(6-Cyclopropylpyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-2-ol

This compound was prepared according to the procedures described inExample 73, using (6-cyclopropylpyridin-3-yl)boronic acid instead of2-((tetrahydrofuran-3-yl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridineas starting material. The product was isolated as the TFA salt. LCMScalculated for C₂₄H₂₃N₄O₂ (M+H)⁺: m/z=399.2; Found: 399.2. ¹H NMR (500MHz, DMSO-d₆) δ 9.47 (d, J=2.2 Hz, 1H), 8.74 (d, J=8.3 Hz, 1H), 7.59 (s,1H), 7.52 (d, J=8.4 Hz, 1H), 7.36-7.31 (m, 1H), 7.29 (d, J=7.1 Hz, 1H),7.25 (t, J=7.4 Hz, 1H), 4.55-4.44 (m, 1H), 3.90 (s, 3H), 3.16 (dd,J=16.0, 6.0 Hz, 1H), 3.04 (dd, J=16.4, 5.9 Hz, 1H), 2.84 (dd, J=16.1,3.8 Hz, 1H), 2.64 (dd, J=16.3, 3.8 Hz, 1H), 2.29-2.17 (m, 1H), 1.15-0.94(m, 4H) ppm.

Example 98.N-(1-(5-(5-(2,3-Dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-3-yl)-2-hydroxy-N-methylacetamide

Step 1.5-(2,3-Dimethylphenyl)-3-(6-fluoropyridin-3-yl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine

To a solution of5-(2,3-dimethylphenyl)-3-iodo-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine(Example 69, Step 1, 255 mg, 0.511 mmol) in 1,4-dioxane (5 mL) and water(0.5 mL) was added2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (219mg, 0.940 mmol), potassium phosphate (312 mg, 1.47 mmol), and[1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (40 mg,0.049 mmol). The reaction was degassed with N₂ and stirred at 80° C. for3 hrs. After this time, it was cooled to r.t. and diluted with EtOAc.The resultant solution was washed sequentially with water, sat. aq. NaClsolution, and dried over Na₂SO₄. The organic phases were filtered andconcentrated to dryness. The residue was purified by Biotage Isolera toafford the desired product. LC-MS calculated for C₂₈H₂₆FN₄O₂ (M+H)⁺:m/z=469.2; found 469.2.

Step 2. tert-Butyl(1-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-3-yl)(methyl)carbamate

To a solution of5-(2,3-dimethylphenyl)-3-(6-fluoropyridin-3-yl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine(120 mg, 0.256 mmol) in DMSO (2.5 mL) was added tert-butylazetidin-3-yl(methyl)carbamate (114 mg, 0.512 mmol) and cesium carbonate(417 mg, 1.22 mmol). The reaction was degassed with N₂ and stirred at100° C. for 5 hrs. After this time, it was cooled to r.t. and dilutedwith EtOAc. The resultant solution was washed sequentially with water,sat. aq. NaCl solution, and dried over Na₂SO₄. The organic phases werefiltered and concentrated to dryness. The residue was purified byBiotage Isolera to afford the desired product. LC-MS calculated forC₃₇H₄₃N₆O₄ (M+H)⁺: m/z=635.2; found 635.2.

Step 3.1-(5-(5-(2,3-Dimethylphenyl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-N-methylazetidin-3-amine

To a solution of tert-butyl(1-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-3-yl)(methyl)carbamate(163 mg, 0.256 mmol) in dichloromethane (0.5 mL) was addedtrifluoroacetic acid (0.5 mL). The reaction was stirred at r.t. for 1hr. After this time, it was diluted with dichloromethane. The resultantsolution was washed sequentially with water, sat. aq. NaCl solution anddried over Na₂SO₄. The organic phases were filtered and concentrated todryness. The residue was used directly in the next step withoutpurification. LC-MS calculated for C₃₂H₃₅N₆O₂ (M+H)⁺: m/z=535.3; found535.2.

Step 4.N-(1-(5-(5-(2,3-Dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-3-yl)-2-hydroxy-N-methylacetamide

To a solution of1-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-N-methylazetidin-3-amine(10 mg, 0.019 mmol) in dichloromethane (0.5 mL) was added2-hydroxyacetic acid (7 mg, 0.09 mmol), trimethylamine (22 mg, 0.17mmol) and HATU (11 mg, 0.028 mmol). The reaction was stirred at r.t. for1 hr. After this time, it was diluted with dichloromethane. Theresultant solution was washed sequentially with water, sat. aq. NaClsolution, and dried over Na₂SO₄. The organic phases were filtered andconcentrated to dryness. The residue was dissolved in dichloromethane(0.5 mL) and trifluoromethanesulfonic acid (0.2 mL). The reaction wasstirred at r.t. After 30 min, the reaction mixture was diluted with MeOHand purified by prep-LCMS (XBridge C18 column, eluting with a gradientof acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min).The product was isolated as the TFA salt. LC-MS calculated forC₂₆H₂₉N₆O₃ (M+H)⁺: m/z=473.2; found 473.2. ¹H NMR (600 MHz, DMSO-d₆) δ13.41 (s, 1H), 9.07 (d, J=2.0 Hz, 1H), 8.66 (d, J=9.2 Hz, 1H), 7.57 (s,1H), 7.24 (dd, J=7.6, 1.4 Hz, 1H), 7.18 (t, J=7.5 Hz, 1H), 7.12 (dd,J=7.6, 1.5 Hz, 1H), 6.98 (t, J=9.9 Hz, 1H), 5.30 (td, J=8.1, 3.8 Hz,1H), 4.44 (t, J=9.0 Hz, 2H), 4.35-4.29 (m, 2H), 4.17 (s, 1H), 4.12 (s,1H), 3.86 (s, 3H), 2.99 (s, 3H), 2.32 (s, 3H), 1.98 (s, 3H) ppm.

Example 99.1-(4-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidin-1-yl)ethan-1-one

Step 1. tert-butyl5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate

tert-Butyl 5-chloro-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate(6.4 g, 22.5 mmol),2-(2,3-dihydro-1H-inden-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(6.0 g, 24.7 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (0.89 g, 1.124 mmol) and Cs₂CO₃ (14.65 g, 45.0 mmol) wereplaced in a 250 ml round-bottom flask and the flask was evacuated andbackfilled with N₂ three times. Dioxane (80 ml) and water (20 ml) wereadded to the mixture and the reaction mixture was stirred at 70° C.overnight. After cooling to r.t., water was added and the desiredproduct was extracted with EtOAc. The organic phase was washed withbrine, dried over sodium sulfate and the solvent was evaporated invacuo. Crude material was purified by Biotage Isolera to give a whitesolid (7.20 g, 88%). LCMS calculated for C₂₁H₂₄N₃O₃ (M+H)⁺: m/z=366.2;found 366.2.

Step 2.5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine

tert-Butyl5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate(7.20 g, 19.7 mmol) in a mixture of DCM (30 ml) and TFA (15.0 ml) wasstirred at r.t. for 1 h. The reaction was then concentrated in vacuo,the residue was dissolved in DCM and neutralized with NaHCO₃ solution.The organic phase was separated, dried over sodium sulfate andconcentrated in vacuo. The obtained crude material was used for nextstep without further purification. LCMS calculated for C₁₆H₁₆N₃O (M+H)⁺:m/z=266.1; found 266.1.

Step 3.5-(2,3-Dihydro-1H-inden-4-yl)-3-iodo-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine

1-Iodopyrrolidine-2,5-dione (6.11 g, 27.1 mmol) was added to a solutionof 5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine(6.00 g, 22.61 mmol) in DMF (60 ml). After stirring at 60° C. for 1 h,the mixture was cooled down to r.t., followed by the addition of cesiumcarbonate (14.74 g, 45.2 mmol) and 1-(chloromethyl)-4-methoxybenzene(3.66 ml, 27.1 mmol). The reaction mixture was stirred at 80° C. for 1h. The reaction mixture was cooled down to r.t., water was added, andthe product was extracted with EtOAc. The organic phase was separated,washed with brine, dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by Biotage Isolera to give a yellow solid. LCMScalculated for C₂₄H₂₃IN₃O₂ (M+H)⁺: m/z 512.2; found 512.2.

Step 4.3-(6-Chloropyridin-3-yl)-5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine

5-(2,3-Dihydro-1H-inden-4-yl)-3-iodo-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine(6.0 g, 11.73 mmol), (6-chloropyridin-3-yl)boronic acid (2.2 g, 14.08mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (0.96 g, 1.173 mmol) and potassiumphosphate (3.24 g, 15.25 mmol) were placed in a 250 ml round-bottomflask and the flask was evacuated and backfilled with N₂ three times.Dioxane (80 ml) and water (20 ml) were transferred to the flask, and thereaction mixture was stirred at 70° C. for 2 hs. After cooling to r.t.,water was added and the desired product was extracted with EtOAc. Theorganic phase was washed with brine, dried over sodium sulfate and thesolvent was evaporated in vacuo. Crude material was purified by BiotageIsolera to give a yellow solid (5.0 g, 86%). LCMS calculated forC₂₉H₂₆ClN₄O₂ (M+H)⁺: m/z=497.2; found 497.2.

Step 5.tert-Butyl-5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-3′,6′-dihydro-[2,4′-bipyridine]-1′(2′H)-carboxylate

3-(6-Chloropyridin-3-yl)-5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine(3.75 g, 7.55 mmol), XPhos Pd G2 (0.6 g, 0.76 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate(3.03 g, 9.81 mmol) and Cs₂CO₃ (4.92 g, 15.09 mmol) were placed in a 250ml round-bottom flask with septum. After the flask was evacuated andbackfilled with N₂ three times, dioxane (80 ml) and water (20 ml) weretransferred to the flask. The reaction mixture was stirred at 70° C. for2 hs. After cooling to r.t., water was added and the desired product wasextracted with EtOAc. The organic phase was washed with brine, driedover sodium sulfate and the solvent was evaporated in vacuo. Crudematerial was purified by Biotage Isolera to give an oil (4.0 g, 82%).LCMS calculated for C₃₉H₄₂N₅O₄ (M+H)⁺: m/z=644.2; found 644.2.

Step 6. tert-Butyl4-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidine-1-carboxylate

A mixture of tert-butyl5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-3′,6′-dihydro-[2,4′-bipyridine]-1′(2′H)-carboxylate(0.80 g, 1.2 mmol) and Pd—C (0.132 g, 0.124 mmol) in MeOH (10 ml) andethyl acetate (10 ml) was stirred in a Parr-Shaker under 30 psi of H₂overnight. Then the reaction mixture was filtered, and the filtrate wasconcentrated in vacuo to give the desired product as colorless oil (0.80g, 99%). LCMS calculated for C₃₉H₄₄N₅O₄ (M+H)⁺: m/z=646.2; found 646.2.

Step 7.5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-3-(6-(piperidin-4-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine

4N Solution of HCl in dioxane (10 ml) was added to a solution oftert-butyl4-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidine-1-carboxylate(0.80 g, 1.24 mmol) in a mixture of EtOAc (5 ml) and methanol (5 ml).The reaction mixture was stirred at r.t for 1 hr, then concentrated todryness in vacuo to give the product as HCl salt (0.80 g, >98%). LCMScalculated for C₃₄H₃₆N₅O₂ (M+H)⁺: m/z=546.2; found 546.2.

Step 8.1-(4-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidin-1-yl)ethan-1-one

A solution of5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-3-(6-(piperidin-4-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine(0.80 g, 1.466 mmol) and triethylamine (0.511 ml, 3.67 mmol) in DCM (5ml) was cooled to 0° C. and acetyl chloride (2.2 ml, 2.2 mmol) was addeddropwise through a syringe. The reaction mixture was stirred at r.t. for1 h, before being quenched with water. The desired product was extractedwith DCM. The organic phase was washed with brine, dried over Na₂SO₄ andthe solvent was removed in vacuo.

The residue was dissolved in DCM (2 ml), and trifluoromethanesulfonicacid (0.66 g, 4.4 mmol) was added. The reaction mixture was stirred atr.t for 1 h. Then the mixture was neutralized with saturated NaHCO₃solution and the product was extracted with DCM. The organic phase waswashed with brine, dried over sodium sulfate and concentrated in vacuo.The mixture was diluted with CH₃CN and purified by prep-LCMS (XBridgeC18 column, eluting with a gradient of acetonitrile/water containing0.1% TFA, at flow rate of 60 mL/min). The product was isolated as theTFA salt. LCMS calculated for C₂₈H₃₀N₅O₂ (M+H)⁺: m/z=468.2; Found:468.2. ¹H NMR (500 MHz, DMSO-d₆) δ 13.49 (s, 1H), 9.56 (d, J=2.1 Hz,1H), 8.80 (d, J=8.3 Hz, 1H), 7.65 (d, J=8.3 Hz, 1H), 7.59 (s, 1H), 7.30(t, J=7.3 Hz, 2H), 7.24 (t, J=7.4 Hz, 1H), 4.55 (d, J=13.2 Hz, 1H), 4.53(d, J=13.2 Hz, 1H), 3.89 (s, 3H), 3.17 (td, J=13.1, 2.7 Hz, 1H), 3.12(m, 1H), 2.96 (t, J=7.4 Hz, 2H), 2.80 (t, J=7.4 Hz, 2H), 2.65 (td,J=12.8, 2.8 Hz, 1H), 2.04 (s, 3H), 2.02-1.86 (m, 4H), 1.74 (qd, J=12.6,4.2 Hz, 1H), 1.59 (qd, J=12.6, 4.3 Hz, 1H) ppm.

Example 100.1-(4-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidin-1-yl)-2-hydroxyethan-1-one

A solution of5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-3-(6-(piperidin-4-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine(1.0 g, 1.83 mmol) (from Example 99, Step 7), 2-hydroxyacetic acid (0.14g, 1.8 mmol), HATU (1.22 g, 2.75 mmol) and DIPEA (0.960 ml, 5.50 mmol)in DMF (10 ml) was stirred at r.t. for 2 hs. Then water was added andthe product was extracted with DCM. The organic phase was washed withbrine and dried over Na₂SO₄. The solution was concentrated in vacuo.

The residue was dissolved in DCM (2 ml), and trifluoromethanesulfonicacid (0.660 g, 4.40 mmol) was added. The reaction mixture was stirred atr.t for 1 h. Then the mixture was neutralized with saturated NaHCO₃solution, and the desired product was extracted with DCM.

The organic phase was washed with brine, dried over sodium sulfate andconcentrated in vacuo. The residue was redissolved in CH₃CN and purifiedby prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). Theproduct was isolated as the TFA salt. LCMS calculated for C₂₈H₃₀N₅O₃(M+H)⁺: m/z=484.2; Found: 484.2. ¹H NMR (500 MHz, DMSO-d₆) δ 13.49 (s,1H), 9.56 (d, J=2.1 Hz, 1H), 8.82 (dd, J=8.1, 2.1 Hz, 1H), 7.63 (d,J=8.3 Hz, 1H), 7.59 (s, 1H), 7.30 (t, J=7.3 Hz, 2H), 7.24 (t, J=7.4 Hz,1H), 4.51 (d, J=13.1 Hz, 1H), 4.14 (t, J=7.4 Hz, 2H), 4.05 (s, 3H), 3.90(t, J=7.4 Hz, 1H), 3.15-2.80 (m, 4H), 2.96 (t, J=7.4 Hz, 1H), 2.83-2.71(m, 3H), 2.03-1.90 (m, 4H), 1.80-1.69 (m, 1H), 1.69-1.58 (m, 1H) ppm.

Example 101.1-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)pyrrolidin-1-yl)-2-hydroxyethan-1-one(Peak 1)

Step 1. tert-Butyl3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate

This compound was prepared according to the procedure described inExample 99, step 5, using tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylateinstead of tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate.LC-MS calculated for C₃₈H₄₀N₅O₄ (M+H)⁺: m/z=630.3; found 630.2.

Step 2. tert-Butyl3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)pyrrolidine-1-carboxylate(Peak 1 and Peak 2)

Racemic mixture of this compound was prepared according to the proceduredescribed in Example 99, step 6, using tert-butyl3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylateinstead oftert-butyl-5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-3′,6′-dihydro-[2,4′-bipyridine]-1′(2′H)-carboxylateas starting material. LC-MS calculated for C₃₈H₄₂N₅O₄ (M+H)⁺: m/z=632.3;found 632.2.

The two enantiomers were separated with chiral prep-SFC (PhenomenexCellulose-5 5 um 21.2×250 mm, eluting with 15% MeOH in CO₂, at flow rateof 90 mL/min, t_(R, peak 1)=4.9 min, t_(R, peak 2)=5.6 min). Peak 1 andPeak 2 were collected and the solvents were evaporated in vacuo. LCMScalculated for C₃₈H₄₂N₅O₄ (M+H)⁺: m/z=632.3; Found: 632.2.

Step 3.5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-3-(6-(pyrrolidin-3-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine(Peak 1 and Peak 2)

These compounds were prepared according to the procedure described inExample 99, step 7, using tert-butyl3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)pyrrolidine-1-carboxylateinstead of tert-butyl4-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidine-1-carboxylate.LC-MS calculated for C₃₃H₃₄N₅O₂ (M+H)⁺: m/z=532.3; found 532.2.

Step 4.1-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)pyrrolidin-1-yl)-2-hydroxyethan-1-one(Peak 1)

This compound was prepared according to the procedure described inExample 100, using5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-3-(6-(pyrrolidin-3-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine(Peak 1) instead of5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-3-(6-(piperidin-4-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridineas starting material. LC-MS calculated for C₂₇H₂₈N₅O₃ (M+H)⁺: m/z=470.2;found 470.2. ¹H NMR (500 MHz, DMSO-d₆) δ 13.43 (s, 1H), 9.56 (d, J=2.1Hz, 1H), 8.73 (td, J=8.1, 7.5, 2.2 Hz, 1H), 7.57 (d, J=15.1 Hz, 2H),7.30 (t, J=7.0 Hz, 2H), 7.24 (t, J=7.4 Hz, 1H), 4.10-3.98 (m, 2H), 3.90(s, 3H), 3.90-3.81 (m, 1H), 3.73-3.60 (m, 3H), 3.51-3.36 (m, 1H), 2.96(t, J=7.4 Hz, 2H), 2.80 (t, J=7.4 Hz, 2H), 2.40-2.13 (m, 2H), 1.98 (p,J=7.4 Hz, 2H) ppm.

Example 102.1-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)pyrrolidin-1-yl)-2-hydroxyethan-1-one(Peak 2)

This compound was prepared according to the procedure described inExample 100, using5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-3-(6-(pyrrolidin-3-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine(Peak 2) instead of5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-3-(6-(piperidin-4-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine.LC-MS calculated for C₂₇H₂₈N₅O₃(M+H)⁺: m/z=470.2; found 470.2.

Example 103.1-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)pyrrolidin-1-yl)ethan-1-one(Peak 1)

This compound was prepared according to the procedure described inExample 99, step 8, using5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-3-(6-(pyrrolidin-3-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine(Peak 1) instead of5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-3-(6-(piperidin-4-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine.LC-MS calculated for C₂₇H₂₈N₅O₂(M+H)⁺: m/z=454.2; found 454.2.

Example 104.1-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)pyrrolidin-1-yl)ethan-1-one(Peak 2)

This compound was prepared according to the procedure described inExample 99, step 8, using5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-3-(6-(pyrrolidin-3-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine(Peak 2) instead of 5-(2,3-dihydro-1H-inden-4-yl)-LC-MS calculated forC₂₇H₂₈N₅O₂(M+H)⁺: m/z=454.2; found 454.2. ¹H NMR (500 MHz, DMSO-d₆) δ13.45 (s, 1H), 9.57 (t, J=2.1 Hz, 1H), 8.76 (ddd, J=10.2, 8.1, 2.2 Hz,1H), 7.62-7.56 (m, 2H), 7.30 (t, J=7.1 Hz, 2H), 7.24 (t, J=7.4 Hz, 1H),3.95-3.83 (m, 4H), 3.74-3.50 (m, 3H), 3.46 (dd, J=11.5, 8.3 Hz, 1H),3.34 (ddd, J=11.6, 9.3, 7.0 Hz, 1H), 2.96 (d, J=14.7 Hz, 2H), 2.80 (t,J=7.3 Hz, 2H), 2.38-2.15 (m, 2H), 2.14-1.94 (m, 4H) ppm.

Example 105.3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-[1,3′-bipyrrolidin]-2′-one(Peak 1)

A mixture of5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-3-(6-(pyrrolidin-3-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine(Peak 1) (15 mg, 0.028 mmol), 3-bromopyrrolidin-2-one (7 mg, 0.042 mmol)and cesium carbonate (18 mg, 0.056 mmol) in 1,4-dioxane (1 ml) and DMF(0.2 ml) was stirred at 70° C. for 2 h. The mixture was cooled to r.t.,quenched with NaHCO₃ solution, and the product was extracted with DCM.The organic phase was washed with brine and dried over Na₂SO₄. Thesolution was concentrated in vacuo.

The residue was dissolved in DCM (0.5 ml), and trifluoromethanesulfonicacid (00.16 g, 1.0 mmol) was added. The reaction mixture was stirred atr.t for 1 h. Then the mixture was neutralized with saturated NaHCO₃solution and the product was extracted with DCM. The organic phase waswashed with brine, dried over sodium sulfate and concentrated in vacuo.The mixture was diluted with CH₃CN and purified by prep-LCMS (XBridgeC18 column, eluting with a gradient of acetonitrile/water containing0.1% TFA, at flow rate of 60 mL/min). The product was isolated as theTFA salt. LCMS calculated for C₂₉H₃₁N₆O₂ (M+H)⁺: m/z=495.2; Found:495.2.

Example 106.3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-1′-methyl-[1,3′-bipyrrolidin]-2′-one(Peak 1)

This compound was prepared according to the procedure described inExample 105, using 3-bromo-1-methylpyrrolidin-2-one instead of3-bromopyrrolidin-2-one. LC-MS calculated for C₃₀H₃₃N₆O₂ (M+H)⁺:m/z=509.3; found 509.2.

Example 107.2-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)pyrrolidin-1-yl)propanamide(Peak 1)

This compound was prepared according to the procedure described inExample 105, using 2-bromopropanamide instead of3-bromopyrrolidin-2-one. LC-MS calculated for C₂₈H₃₁N₆O₂(M+H)⁺:m/z=483.2; found 483.2.

Example 108.5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-3-(6-(1-(methyl-L-prolyl)piperidin-4-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine

This compound was prepared according to the procedure described inExample 100, using methyl-L-proline instead of 2-hydroxyacetic acid.LC-MS calculated for C₃₂H₃₇N₆O₂ (M+H)⁺: m/z=537.3; found 537.3.

Example 109.(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)pyrrolidin-1-yl)((R)-4-methylmorpholin-3-yl)methanone(Peak 2)

This compound was prepared according to the procedure described inExample 102, using (R)-4-methylmorpholine-3-carboxylic acid instead of2-hydroxyacetic acid. LC-MS calculated for C₃₁H₃₅N₆O₃(M+H)⁺: m/z=539.3;found 539.3.

Example 110.4-(6-Methoxy-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile

Step 1.4-(3-Iodo-6-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-JH-indene-1-carbonitrile

NIS (2.01 g, 8.96 mmol) was added to a solution of4-(6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile(2.6 g, 8.96 mmol) in DMF (60 ml). After stirring at 60° C. for 2 h, thereaction mixture was cooled to r.t., and DIEA (3.13 ml, 17.91 mmol) andSEM-Cl (2.4 ml, 13.43 mmol) were added. After additional stirring atr.t. for 12 hs, water was added and the product was extracted withEtOAc. The combined organic phases were washed with sat. NaCl solution,dried over Na₂SO₄, filtered, concentrated to dryness and purified byflash column chromatography to afford the desired product. LC-MScalculated for C₂₃H₂₈IN₄O₂Si (M+H)⁺: m/z=547.1; found 547.1.

Step 2.4-(6-Methoxy-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile

4-(3-Iodo-6-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile(50 mg, 0.091 mmol),1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine(42 mg, 0.137 mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (8 mg, 9.68 μmol), andNa₂CO₃ (20 mg, 0.183 mmol) were placed in a vial and the vial wasevacuated and backfilled with N₂ three times. After 1,4-dioxane (1 ml)and water (100 μl) were added, the reaction mixture was stirred at 80°C. for 1 h. Then the reaction was filtered, and the solvents wereevaporated in vacuo. DCM (1 ml) and TFA (0.5 ml) were added and thereaction mixture was stirred at r.t. for 30 min. The reaction was thenconcentrated and 1 mL of MeOH and ammonium hydroxide solution wereadded, the mixture was stirred for 10 min and then diluted with CH₃CNand water and purified with prep-LCMS (XBridge C18 column, eluting witha gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min). The product was isolated as the TFA salt. LC-MS calculated forC₂₇H₂₈N₇O (M+H)⁺: m/z=466.2; found 466.2.

Example 111.4-(3-(1-(3-Cyanocyclobutyl)-1H-pyrazol-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile

This compound was prepared according to the procedures described inExample 110, using3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrileinstead of1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazinein step 2. The product was isolated as the TFA salt. LCMS calculated forC₂₅H₂₂N₇O (M+H)⁺: m/z=436.2; Found: 436.2.

Example 112.4-(3-(1-(1-Acetylpiperidin-4-yl)-1H-pyrazol-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile

This compound was prepared according to the procedures described inExample 110, using1-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethan-1-oneinstead of1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazinein step 2. The product was isolated as the TFA salt. LCMS calculated forC₂₇H₂₈N₇O₂ (M+H)⁺: m/z=482.2; Found: 482.2.

Example 113.4-(3-(6-(4-Hydroxycyclohexyl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile

Step 1.4-(3-(6-Chloropyridin-3-yl)-6-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile

4-(3-Iodo-6-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile(400 mg, 0.732 mmol), (6-chloropyridin-3-yl)boronic acid (127 mg, 0.805mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (60 mg, 0.073 mmol) and K₃PO₄ (310 mg,1.46 mmol) were placed in a vial with septum. The vial was evacuated andbackfilled with N₂ three times, 1,4-dioxane (10 mL) and water (2 mL)were added, and the reaction mixture was stirred at 80° C. for 1 h. Themixture was filtered. The filtrate was partitioned between water andEtOAc. The organic phase was separated, washed with brine, dried overNa₂SO₄, filtered and concentrated. The residue was purified by BiotageIsolera to afford the desired product. LC-MS calculated forC₂₈H₃₁ClN₅O₂Si (M+H)⁺: m/z=532.2; found 532.1.

Step 2.4-(3-(6-(4-Hydroxycyclohex-1-en-1-yl)pyridin-3-yl)-6-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile

4-(3-(6-Chloropyridin-3-yl)-6-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile(50 mg, 0.094 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-ol (32mg, 0.141 mmol), Xphos-PdG2 (8 mg, 9.40 μmol) and K₃PO₄ (40 mg, 0.188mmol) were placed in a vial with septum. The vial was evacuated andbackfilled with N₂ three times, 1,4-dioxane (1 mL) and water (0.2 mL)were added, and the reaction mixture was stirred at 100° C. for 1 h. Themixture was filtered.

The filtrate was partitioned between water and EtOAc. The organic phasewas separated, washed with brine, dried over Na₂SO₄, filtered andconcentrated. The residue was purified by Biotage Isolera to afford thedesired product. LC-MS calculated for C₃₄H₄₀N₅O₃Si (M+H)⁺: m/z=594.3;found 594.3.

Step 3.4-(3-(6-(4-Hydroxycyclohexyl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile

A mixture of4-(3-(6-(4-hydroxycyclohex-1-en-1-yl)pyridin-3-yl)-6-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile(35 mg, 0.059 mmol) and palladium on carbon (6 mg, 10%) in methanol (5mL) was connected to a balloon filled with hydrogen and the reactionmixture was stirred at r.t. for 3 hrs. The reaction mixture was thenfiltered and concentrated in vacuo. 4N HCl solution in dioxane was thenadded and the reaction was stirred at r.t. for 30 min. It was thendiluted with methanol and purified by prep-LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min). LC-MS calculated for C₂₈H₂₈N₅O₂ (M+H)⁺:m/z=466.2, found 466.2.

Example 114.4-(3-(6-(4-(2-Hydroxyethyl)piperazin-1-yl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile

This compound was prepared according to the procedures described inExample 110, using2-(4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazin-1-yl)ethan-1-olinstead of1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazinein step 2. The product was isolated as the TFA salt. LCMS calculated forC₂₈H₃₀N₇O₂ (M+H)⁺: m/z=496.2; Found: 496.2. ¹H NMR (500 MHz, DMSO-d₆) δ13.2 (1H, s), 9.22 (d, J=1.6 Hz, 1H), 8.52 (dd, J=8.9, 1.9 Hz, 1H), 7.56(s, 1H), 7.49 (d, J=7.6 Hz, 2H), 7.41 (t, J=7.5 Hz, 1H), 7.11 (d, J=8.9Hz, 1H), 4.57 (t, J=8.0 Hz, 1H), 4.44 (d, J=13.6 Hz, 2H), 3.90 (s, 3H),3.81-3.75 (m, 2H), 3.60 (d, J=11.6 Hz, 2H), 3.31 (m, 4H), 3.17-3.12 (m,2H), 2.90 (m, 2H), 2.56 (m, 1H), 2.21 (m, 1H) ppm.

Example 115.4-(3-(6-(1-(2-Hydroxyacetyl)piperidin-4-yl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile

Step 1. tert-butyl5-(5-(1-Cyano-2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-3′,6′-dihydro-[2,4′-bipyridine]-1′(2′H)-carboxylate

A mixture of4-(3-iodo-6-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile(600 mg, 1.098 mmol), tert-butyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3′,6′-dihydro-[2,4′-bipyridine]-1′(2′H)-carboxylate(467 mg, 1.208 mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (90 mg, 0.110 mmol) andK₃PO₄ (466 mg, 2.2 mmol) in 1,4-dioxane (6 mL) and water (0.6 mL) wasstirred at 80° C. overnight. After cooling to r.t., the reaction mixturewas filtered and the solvent was evaporated in vacuo. The crude materialwas dissolved in methanol and purified by Biotage Isolera to afford thedesired product. LC-MS calculated for C₃₈H₄₇N₆O₄Si (M+H)⁺: m/z=679.3;found 679.3.

Step 2.4-(6-Methoxy-3-(6-(piperidin-4-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile

A mixture of tert-butyl5-(5-(1-cyano-2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-3′,6′-dihydro-[2,4′-bipyridine]-1′(2′H)-carboxylate(150 mg, 0.221 mmol) and palladium on carbon (23 mg, 10%) in methanol (5mL) was connected to a balloon filled with hydrogen and the reactionmixture was stirred at r.t. for 3 hrs. The reaction mixture was thenfiltered and concentrated in vacuo. 4N HCl solution in dioxane was thenadded and the reaction was stirred at r.t. for 30 min. It was thendiluted with methanol and purified by prep-LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min). LC-MS calculated for C₂₇H₂₇N₆O (M+H)⁺:m/z=451.2, found 451.2.

Step 3.4-(3-(6-(1-(2-Hydroxyacetyl)piperidin-4-yl)pyridin-3-yl)-6-methoxy-M-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-M-indene-1-carbonitrile

HATU (63 mg, 0.166 mmol) was added to a solution of 2-hydroxyacetic acid(13 mg, 0.166 mmol),4-(6-methoxy-3-(6-(piperidin-4-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile(50 mg, 0.111 mmol) and DIEA (39 μl, 0.222 mmol) in DMF (1 mL). Afterstirring at r.t. for 1 h, the reaction mixture was diluted withmethanol, filtered and purified with prep-LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min). The product was isolated as the TFA salt. LC-MScalculated for C₂₉H₂₉N₆O₃ (M+H)⁺: m/z=509.2, found 509.3. ¹H NMR (500MHz, DMSO-d₆) δ 13.5 (s, 1H), 9.53 (s, 1H), 8.76 (d, J=7.9 Hz, 1H), 7.62(s, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.50 (d, J=7.6 Hz, 2H), 7.41 (t, J=7.5Hz, 1H), 4.57 (t, J=8.0 Hz, 1H), 4.51 (d, J=11.9 Hz, 1H), 4.13 (q,J=14.8 Hz, 2H), 3.91 (s, 3H), 3.82 (d, J=12.6 Hz, 1H), 3.13-3.03 (m,2H), 2.93 (m, 2H), 2.75 (t, J=12.4 Hz, 1H), 2.56 (m, 1H), 2.22 (dd,J=12.5, 8.2 Hz, 1H), 1.93 (d, J=12.3 Hz, 2H), 1.62 (m, 2H) ppm.

Example 116.1-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-2-hydroxyethan-1-one

Step 1.3-(1-(Azetidin-3-yl)-1H-pyrazol-4-yl)-5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine

This compound was prepared according to the procedures described inExample 129, using tert-butyl3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylateinstead of tert-butyl(S)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylateas starting material. LC-MS calculated for C₂₂H₂₃N₆O (M+H)⁺: m/z=387.2;found 387.2.

Step 2.1-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-2-hydroxyethan-1-one

A solution of3-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine(10 mg, 0.026 mmol), 2-hydroxyacetic acid (2 mg, 0.026 mmol), BOPreagent (17 mg, 0.04 mmol) and DIPEA (14 μl. 0.078 mmol) in DMF (0.4 ml)was stirred at r.t. for 1 hour. Then to the mixture was added 0.1 ml of1N NaOH solution. The reaction mixture was stirred at 40° C. for 1 h.The reaction mixture was then diluted with MeOH and purified byprep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). Theproduct was isolated as the TFA salt. LC-MS calculated for C₂₄H₂₅N₆O₃(M+H)⁺: m/z=445.2; found 445.1. ¹H NMR (500 MHz, DMSO-d₆) δ 8.47 (d,J=1.8 Hz, 1H), 8.22 (d, J=1.8 Hz, 1H), 7.48 (d, J=1.9 Hz, 1H), 7.28 (t,J=7.7 Hz, 2H), 7.25-7.19 (m, 1H), 5.44 (ddd, J=12.7, 7.7, 4.9 Hz, 1H),4.65 (t, J=8.8 Hz, 1H), 4.51 (dd, J=9.7, 5.3 Hz, 1H), 4.36 (t, J=9.2 Hz,1H), 4.20 (dd, J=10.3, 5.3 Hz, 1H), 3.97 (d, J=1.8 Hz, 2H), 3.87 (d,J=1.8 Hz, 3H), 2.95 (t, J=7.5 Hz, 2H), 2.80 (t, J=7.4 Hz, 2H), 1.98 (p,J=7.3 Hz, 2H) ppm.

Example 117.1-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-3-(dimethylamino)propan-1-one

This compound was prepared according to the procedures described inExample 116, using 3-(dimethylamino)propanoic acid instead of2-hydroxyacetic acid as starting material. The product was isolated asthe TFA salt. LC-MS calculated for C₂₇H₃₂N₇O₂ (M+H)⁺: m/z=486.2; found486.3.

Example 118.(S)-1-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-2-(dimethylamino)propan-1-one

This compound was prepared according to the procedures described inExample 116, using dimethyl-L-alanine instead of 2-hydroxyacetic acid asstarting material. The product was isolated as the TFA salt. LC-MScalculated for C₂₇H₃₂N₇O₂ (M+H)⁺: m/z=486.2; found 486.3. ¹H NMR (500MHz, DMSO-d₆) δ 9.81 (s, 1H), 8.52 (dd, J=8.3, 1.8 Hz, 1H), 8.25 (d,J=1.8 Hz, 1H), 7.49 (d, J=1.9 Hz, 1H), 7.28 (dd, J=12.5, 7.4 Hz, 2H),7.22 (t, J=7.4 Hz, 1H), 5.48 (m, 1H), 4.80 (t, J=8.9 Hz, 1H), 4.74-4.63(m, 1H), 4.58-4.41 (m, 1H), 4.29 (m, 1H), 4.13 (q, J=6.8 Hz, 1H), 3.87(d, J=1.7 Hz, 3H), 2.95 (t, J=7.4 Hz, 2H), 2.80 (d, J=4.0 Hz, 6H), 1.98(p, J=7.4 Hz, 2H), 1.44 (dd, J=7.0, 1.8 Hz, 3H) ppm.

Example 119.(S)-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(1-methylazetidin-2-yl)methanone

This compound was prepared according to the procedures described inExample 116, using (S)-1-methylazetidine-2-carboxylic acid instead of2-hydroxyacetic acid as starting material. The product was isolated asthe TFA salt. LC-MS calculated for C₂₇H₃₀N₇O₂ (M+H)⁺: m/z=484.2; found484.2.

Example 120.1-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-2-(4-methylpiperazin-1-yl)ethan-1-one

This compound was prepared according to the procedures described inExample 116, using 2-(4-methylpiperazin-1-yl)acetic acid instead of2-hydroxyacetic acid as starting material. The product was isolated asthe TFA salt. LC-MS calculated for C₂₉H₃₅N₈O₂ (M+H)⁺: m/z=527.3; found527.3.

Example 121.1-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-2-(4-hydroxypiperidin-1-yl)ethan-1-one

This compound was prepared according to the procedures described inExample 116, using 2-(4-hydroxypiperidin-1-yl)acetic acid instead of2-hydroxyacetic acid as starting material. The product was isolated asthe TFA salt. LC-MS calculated for C₂₇H₃₄N₇O₃ (M+H)⁺: m/z=528.3; found528.2.

Example 122.(R)-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(1-methylazetidin-2-yl)methanone

This compound was prepared according to the procedures described inExample 116, using (R)-1-methylazetidine-2-carboxylic acid instead of2-hydroxyacetic acid as starting material. The product was isolated asthe TFA salt. LC-MS calculated for C₂₇H₃₀N₇O₂ (M+H)⁺: m/z=484.2; found484.2.

Example 123.(R)-1-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-2-hydroxypropan-1-one

This compound was prepared according to the procedures described inExample 116, using (R)-2-hydroxypropanoic acid instead of2-hydroxyacetic acid as starting material. The product was isolated asthe TFA salt. LC-MS calculated for C₂₅H₂₇N₆O₃ (M+H)⁺: m/z=459.2; found459.2 ¹H NMR (500 MHz, DMSO-d₆) δ 8.47 (s, 1H), 8.22 (d, J=1.6 Hz, 1H),7.48 (d, J=1.7 Hz, 1H), 7.28 (t, J=7.9 Hz, 2H), 7.22 (t, J=7.1 Hz, 1H),5.43 (m, 1H), 4.72 (m, 1H), 4.62-4.53 (m, 1H), 4.33 (dt, J=17.0, 9.2 Hz,1H), 4.23-4.12 (m, 2H), 3.87 (d, J=1.7 Hz, 3H), 2.95 (t, J=7.4 Hz, 2H),2.80 (t, J=7.4 Hz, 2H), 1.98 (p, J=7.3 Hz, 2H), 1.21 (dd, J=6.7, 1.7 Hz,3H).

Example 124.(S)-1-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-2-hydroxypropan-1-one

This compound was prepared according to the procedures described inExample 116, using (S)-2-hydroxypropanoic acid instead of2-hydroxyacetic acid as starting material. The product was isolated asthe TFA salt. LC-MS calculated for C₂₅H₂₇N₆O₃ (M+H)⁺: m/z=459.2; found459.2.

Example 125.(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)((trans)-3-hydroxycyclobutyl)methanone

This compound was prepared according to the procedures described inExample 116, using (trans)-3-hydroxycyclobutane-1-carboxylic acidinstead of 2-hydroxyacetic acid as starting material. The product wasisolated as the TFA salt. LC-MS calculated for C₂₇H₂₈N₆O₃ (M+H)⁺:m/z=485.2; found 485.2.

Example 126.(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)((cis)-3-hydroxycyclobutyl)methanone

This compound was prepared according to the procedures described inExample 116, using (cis)-3-hydroxycyclobutane-1-carboxylic acid insteadof 2-hydroxyacetic acid as starting material. LC-MS calculated forC₂₇H₂₉N₆O₃ (M+H)⁺: m/z=485.2; found 485.2. ¹H NMR (600 MHz, DMSO-d₆) δ8.47 (s, 1H), 8.21 (s, 1H), 7.48 (s, 1H), 7.28 (t, J=8.2 Hz, 2H), 7.22(t, J=7.4 Hz, 1H), 5.41 (m, 1H), 4.52 (t, J=8.5 Hz, 1H), 4.38 (dd,J=9.1, 5.3 Hz, 1H), 4.29 (dd, J=9.9, 8.2 Hz, 1H), 4.14 (dd, J=10.1, 5.3Hz, 1H), 3.95 (m, 1H), 3.87 (s, 3H), 2.95 (t, J=7.4 Hz, 2H), 2.80 (t,J=7.4 Hz, 2H), 2.56-2.46 (m, 1H), 2.31 (m, 2H), 2.02-1.90 (m, 4H).

Example 127.(R)-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(4-methylmorpholin-3-yl)methanone

This compound was prepared according to the procedures described inExample 116, using (R)-4-methylmorpholine-3-carboxylic acid instead of2-hydroxyacetic acid as starting material. The product was isolated asthe TFA salt. LC-MS calculated for C₂₈H₃₂N₇O₃ (M+H)⁺: m/z=514.2; found514.2.

Example 128.(S)-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(4-methylmorpholin-3-yl)methanone

This compound was prepared according to the procedures described inExample 116, using (S)-4-methylmorpholine-3-carboxylic acid instead of2-hydroxyacetic acid as starting material. The product was isolated asthe TFA salt. LC-MS calculated for C₂₈H₃₂N₇O₃ (M+H)⁺: m/z=514.2; found514.2.

Example 129.(S)-1-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)-2-hydroxyethan-1-one

Step 1.5-(2,3-Dihydro-1H-inden-4-yl)-3-iodo-6-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine

To a solution of5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine (2.20g, 8.29 mmol) in DMF (26 ml) was added N-iodosuccinimide (2.80 g, 12.44mmol), and the reaction mixture was stirred at 60° C. for 1 h. Afterbeing cooled down with the ice bath, to the reaction mixture was addedDIPEA (1.7 ml, 9.95 mmol), followed by SEM-Cl (1.62 ml, 9.12 mmol). Thereaction mixture was stirred at r.t. for 2 h. Then it was quenched withwater, and the desired product was extracted with EtOAc. The organicphase was washed with sat. Na₂S₂O₃ solution, dried over Na₂SO₄,concentrated in vacuo, and the residue was purified by Biotage Isolera.The purification gave the desired product as oil. LC-MS calculated forC₂₂H₂₉IN₃O₂Si (M+H)⁺: m/z=522.1; found 522.1.

Step 2.(S)-5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-3-(1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine

5-(2,3-Dihydro-1H-inden-4-yl)-3-iodo-6-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine(440 mg, 0.844 mmol), tert-butyl(S)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate(400 mg, 1.1 mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (66 mg, 0.084 mmol) and K₃PO₄ (358 mg, 1.688 mmol) were placed ina vial with septum. After 3 times vacuum/N₂, 1,4-dioxane (6 mL) andwater (1 mL) were added, and the reaction mixture was stirred at 60° C.for 1 h. Then it was cooled to r.t. and diluted with EtOAc/water. Theorganic phase was washed with brine, dried over Na₂SO₄, concentrated invacuo, and the residue was purified by Biotage Isolera.

TFA (5 ml) and DCM (5 ml) were added to the obtained material and thereaction was stirred at r.t. for 1 h. Then it was concentrated in vacuoand redissolved in MeOH (5 ml). The concentrated water ammonia solution(1 ml) was added and the reaction was stirred at r.t. for 1 h. Thenwater was added, and the product was extracted with DCM. The organicphase was washed with brine, dried over Na₂SO₄ and concentrated to givethe desired product. LC-MS calculated for C₂₃H₂₅N₆O (M+H)⁺: m/z=401.2;found 401.2.

Step 3.(S)-1-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)-2-hydroxyethan-1-one

This compound was prepared according to the procedures described inExample 116, using(S)-5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-3-(1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridineinstead of3-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridineas starting material. The product was isolated as the TFA. LC-MScalculated for C₂₅H₂₇N₆O₃ (M+H)⁺: m/z=459.2; found 459.2. ¹H NMR (500MHz, DMSO-d₆) δ 8.41 (m, 1H), 8.14 (m, 1H), 7.48 (d, J=1.9 Hz, 1H), 7.29(d, J=7.4 Hz, 2H), 7.26-7.19 (m, 1H), 5.18-5.12 (m, 1H), 4.04 (s, 1H),4.00 (s, 1H), 3.90 (t, J=5.6 Hz, 2H), 3.87 (s, 3H), 3.78-3.61 (m, 2H),3.57-3.52 (m, 1H), 3.52-3.46 (m, 1H), 2.95 (t, J=7.4 Hz, 2H), 2.81 (t,J=7.4 Hz, 2H), 2.46-2.24 (m, 2H), 1.98 (p, J=7.4 Hz, 2H).

Example 130.(S)-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(tetrahydrofuran-2-yl)methanone

This compound was prepared according to the procedures described inExample 116, using (S)-tetrahydrofuran-2-carboxylic acid instead of2-hydroxyacetic acid as starting material. The product was isolated asthe TFA salt. LC-MS calculated for C₂₇H₂₉N₆O₃ (M+H)⁺: m/z=485.2; found485.4.

Example 131.(S)-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(tetrahydrofuran-3-yl)methanone

This compound was prepared according to the procedures described inExample 116, using (S)-tetrahydrofuran-3-carboxylic acid instead of2-hydroxyacetic acid as starting material. The product was isolated asthe TFA salt. LC-MS calculated for C₂₇H₂₉N₆O₃ (M+H)⁺: m/z=485.2; found485.4.

Example 132.(R)-1-((S)-3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)-2-hydroxypropan-1-one

This compound was prepared according to the procedures described inExample 129, using (R)-2-hydroxypropanoic acid instead of2-hydroxyacetic acid as starting material. The product was isolated asthe TFA salt. LC-MS calculated for C₂₆H₂₉N₆O₃ (M+H)⁺: m/z=473.2; found473.2.

Example 133.(S)-1-((S)-3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)-2-hydroxypropan-1-one

This compound was prepared according to the procedures described inExample 129, using (S)-2-hydroxypropanoic acid instead of2-hydroxyacetic acid as starting material. The product was isolated asthe TFA salt. LC-MS calculated for C₂₆H₂₉N₆O₃ (M+H)⁺: m/z=473.2; found473.2.

Example 134.(R)-1-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-3-hydroxybutan-1-one

This compound was prepared according to the procedures described inExample 116, using (R)-3-hydroxybutanoic acid instead of 2-hydroxyaceticacid as starting material. The product was isolated as the TFA salt.LC-MS calculated for C₂₆H₂₉N₆O₃ (M+H)⁺: m/z=473.2; found 473.2.

Example 135.(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)((1r,3r)-3-hydroxy-3-methylcyclobutyl)methanone

This compound was prepared according to the procedures described inExample 116, using (1r,3r)-3-hydroxy-3-methylcyclobutane-1-carboxylicacid as starting material. LC-MS calculated for C₂₈H₃₁N₆O₃ (M+H)⁺:m/z=499.2; found 499.2.

Example 136.(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)((1s,3s)-3-hydroxy-3-methylcyclobutyl)methanone

This compound was prepared according to the procedures described inExample 116, using (1s,3s)-3-hydroxy-3-methylcyclobutane-1-carboxylicacid instead of 2-hydroxyacetic acid as starting material. The productwas isolated as the TFA salt. LC-MS calculated for C₂₈H₃₁N₆O₃ (M+H)⁺:m/z=499.2; found 499.2. ¹H NMR (600 MHz, DMSO-d₆) δ 8.47 (s, 1H), 8.22(s, 1H), 7.48 (s, 1H), 7.28 (t, J=7.5 Hz, 2H), 7.22 (t, J=7.4 Hz, 1H),5.41 (m, 1H), 4.52 (t, J=8.6 Hz, 1H), 4.39 (dd, J=9.1, 5.2 Hz, 1H), 4.30(dd, J=10.0, 8.1 Hz, 1H), 4.14 (dd, J=10.1, 5.3 Hz, 1H), 3.87 (s, 3H),2.95 (t, J=7.4 Hz, 2H), 2.80 (t, J=7.3 Hz, 2H), 2.67-2.58 (m, 1H), 2.15(m, 2H), 2.04 (m, 2H), 1.98 (p, J=7.4 Hz, 2H), 1.25 (s, 3H).

Example 137.((R)-3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)((S)-4-methylmorpholin-3-yl)methanone

Step 1.(R)-5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-3-(1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine

This compound was prepared according to the procedures described inExample 129 (step 2) using(R)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylateinstead of(S)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylateas starting material. LC-MS calculated for C₂₃H₂₅N₆O (M+H)⁺: m/z=401.2;found 401.2.

Step 2.((R)-3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)((S)-4-methylmorpholin-3-yl)methanone

This compound was prepared according to the procedures described inExample 116, using(R)-5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-3-(1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridineinstead of3-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridineand (S)-4-methylmorpholine-3-carboxylic acid instead of 2-hydroxyaceticacid as starting material. The product was isolated as the TFA. LC-MScalculated for C₂₉H₃₄N₇O₃ (M+H)⁺: m/z=528.3; found 528.3.

Example 138.((S)-3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)((R)-4-methylmorpholin-3-yl)methanone

This compound was prepared according to the procedures described inExample 129, using (R)-4-methylmorpholine-3-carboxylic acid instead of2-hydroxyacetic acid as starting material. The product was isolated asthe TFA salt. LC-MS calculated for C₂₉H₃₄N₇O₃ (M+H)⁺: m/z=528.3; found528.3.

Example 139.(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(1-(hydroxymethyl)cyclobutyl)methanone

This compound was prepared according to the procedures described inExample 116, using 1-(hydroxymethyl)cyclobutane-1-carboxylic acidinstead of 2-hydroxyacetic acid as starting material. The product wasisolated as the TFA salt. LC-MS calculated for C₂₈H₃₁N₆O₃ (M+H)⁺:m/z=499.2; found 499.3.

Example 140.(S)-(3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(1-ethylazetidin-2-yl)methanone

This compound was prepared according to the procedures described inExample 116, using (S)-1-ethylazetidine-2-carboxylic acid instead of2-hydroxyacetic acid as starting material. The product was isolated asthe TFA salt. LC-MS calculated for C₂₈H₃₂N₇O₂ (M+H)⁺: m/z=498.2; found498.2.

Example 141.(S)-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(1-(2-fluoroethyl)azetidin-2-yl)methanone

This compound was prepared according to the procedures described inExample 116, using (S)-1-(2-fluoroethyl)azetidine-2-carboxylic acidinstead of 2-hydroxyacetic acid as starting material. The product wasisolated as the TFA salt. LC-MS calculated for C₂₈H₃₁FN₇O₂ (M+H)⁺:m/z=516.2; found 516.2.

Example 142.(S)-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(1-isopropylazetidin-2-yl)methanone

This compound was prepared according to the procedures described inExample 116, using (S)-1-isopropylazetidine-2-carboxylic acid instead of2-hydroxyacetic acid as starting material. The product was isolated asthe TFA salt. LC-MS calculated for C₂₉H₃₄N₇O₂(M+H)⁺: m/z=512.3; found512.3.

Example 143.((S)-3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)((S)-1-(2-fluoroethyl)azetidin-2-yl)methanone

This compound was prepared according to the procedures described inExample 129, using (S)-1-(2-fluoroethyl)azetidine-2-carboxylic acidinstead of 2-hydroxyacetic acid as starting material. The product wasisolated as the TFA salt. LC-MS calculated for C₂₉H₃₃FN₇O₂(M+H)⁺:m/z=530.3; found 530.3.

Example 144.((S)-3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)((trans)-3-hydroxycyclobutyl)methanone

This compound was prepared according to the procedures described inExample 129, using (trans)-3-hydroxycyclobutane-1-carboxylic acidinstead of 2-hydroxyacetic acid as starting material. The product wasisolated as the TFA salt. LC-MS calculated for C₂₈H₃₁N₆O₃(M+H)⁺:m/z=499.2; found 499.3.

Example 145.((S)-3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)((cis)-3-hydroxycyclobutyl)methanone

This compound was prepared according to the procedures described inExample 129, using (cis)-3-hydroxycyclobutane-1-carboxylic acid insteadof 2-hydroxyacetic acid as starting material. The product was isolatedas the TFA salt. LC-MS calculated for C₂₈H₃₁N₆O₃(M+H)⁺: m/z=499.2; found499.2.

Example 146.((S)-3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)((1s,3r)-3-hydroxy-3-methylcyclobutyl)methanone

This compound was prepared according to the procedures described inExample 129, using, (1s,3s)-3-hydroxy-3-methylcyclobutane-1-carboxylicacid instead of 2-hydroxyacetic acid as starting material. The productwas isolated as the TFA salt. LC-MS calculated for C₂₉H₃₃N₆O₃(M+H)⁺:m/z=513.2; found 513.2.

Example 147.1-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-2-methoxyethan-1-one

This compound was prepared according to the procedures described inExample 116, using 2-methoxyacetic acid instead of 2-hydroxyacetic acidas starting material. The product was isolated as the TFA salt. LC-MScalculated for C₂₅H₂₇N₆O₃(M+H)⁺: m/z=459.2; found 459.2.

Example 148.1-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-2-(dimethylamino)-2-methylpropan-1-one

This compound was prepared according to the procedures described inExample 116, using 2-(dimethylamino)-2-methylpropanoic acid instead of2-hydroxyacetic acid as starting material. The product was isolated asthe TFA salt. LC-MS calculated for C₂₈H₃₄N₇O₂ (M+H)⁺: m/z=500.2; found500.2.

Example 149.1-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidine-1-carbonyl)cyclopropane-1-carbonitrile

This compound was prepared according to the procedures described inExample 116, using 1-cyanocyclopropane-1-carboxylic acid instead of2-hydroxyacetic acid as starting material. The product was isolated asthe TFA salt. LC-MS calculated for C₂₇H₂₆N₇O₂(M+H)⁺: m/z=480.2; found480.2.

Example 150.2-((3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)sulfonyl)ethan-1-ol

Step 1.3-(1-(Azetidin-3-yl)-1H-pyrazol-4-yl)-5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine

5-(2,3-Dihydro-1H-inden-4-yl)-3-iodo-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine(0.8 g, 1.56 mmol), tert-butyl3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate(0.71 g, 2.03 mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (0.12 g, 0.156 mmol) and cesium carbonate (0.66 g, 2.03 mmol) wereplaced in a vial with septum. After 3 times vacuum/N₂1,4-dioxane (10 mL)and water (2 mL) were added, and the reaction mixture was stirred at 60°C. for 1 h. Then it was cooled to r.t. and diluted with EtOAc/water. Theorganic phase separated, washed with brine, dried over Na₂SO₄,concentrated in vacuo, and the residue was purified by Biotage Isolera.

TFA (5 ml) and DCM (5 ml) were added to the obtained intermediate, andthe reaction mixture was stirred at r.t. for 1 h. Then it wasconcentrated in vacuo, and the reaction was neutralized with thesaturated NaHCO₃ solution. The product was extracted with DCM. Theorganic phase was washed with brine, dried over Na₂SO₄ and concentratedto give the desired product. LC-MS calculated for C₃₀H₃₁N₆O₂ (M+H)⁺:m/z=507.2; found 507.2.

Step 2.2-((3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)sulfonyl)ethan-1-ol

To a solution of3-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine(10 mg, 0.020 mmol) and TEA (6 μl, 0.04 mmol) in DCM (1 ml) at 0° C. wasadded 2-hydroxyethane-1-sulfonyl chloride (3 mg, 0.020 mmol). Thereaction mixture was stirred at r.t. for 1 h. Then it was quenched withbrine, and the product was extracted with DCM. The organic phase wasdried over sodium sulfate and concentrated in vacuo.

The residue was dissolved in DCM (0.5 ml), and trifluoromethanesulfonicacid (0.2 ml) was added. The reaction mixture was stirred at r.t for 1h. Then the mixture was neutralized with saturated NaHCO₃ solution andthe product was extracted with DCM. The organic phase was washed withbrine, dried over sodium sulfate and concentrated in vacuo. The mixturewas diluted with CH₃CN and purified by prep-LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min). The product was isolated as the TFA salt. LC-MScalculated for C₂₄H₂₇N₆O₄S (M+H)⁺: m/z=495.2; found 495.1.

Example 151.2-((3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)sulfonyl)-N,N-dimethylethan-1-amine

This compound was prepared according to the procedures described inExample 150, using 2-(dimethylamino)ethane-1-sulfonyl chloride insteadof 2-hydroxyethane-1-sulfonyl chloride as starting material. The productwas isolated as the TFA salt. LC-MS calculated for C₂₆H₃₂N₇O₃S (M+H)⁺:m/z=522.2; found 522.2.

Example 152. 2-Methoxyethyl3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate

This compound was prepared according to the procedures described inExample 150, using 2-methoxyethyl carbonochloridate instead of2-hydroxyethane-1-sulfonyl chloride as starting material. The productwas isolated as the TFA salt. LC-MS calculated for C₂₆H₂₉N₆O₄ (M+H)⁺:m/z=489.2; found 489.2.

Example 153.(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)((1s,3s)-3-methoxycyclobutyl)methanone

This compound was prepared according to the procedures described inExample 116, using (1s, 3 s)-3-methoxycyclobutane-1-carboxylic acidinstead of 2-hydroxyacetic acid as starting material. The product wasisolated as the TFA salt. LC-MS calculated for C₂₈H₃₁N₆O₃ (M+H)⁺:m/z=499.2; found 499.2.

Example 154.N-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclopentyl)-N-methylmethanesulfonamide

Step 1.3-(6-Bromopyridin-3-yl)-5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine

5-(2,3-Dihydro-1H-inden-4-yl)-3-iodo-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine(3.5 g, 6.84 mmol), (6-bromopyridin-3-yl)boronic acid (2.5 g, 12.32mmol), Pd(dppf)₂Cl₂ (1.5 g) and Cs₂CO₃ (3.5 g) in dioxane (35 mL) andwater (8 mL) were mixed together. The reaction mixture was purged withnitrogen and heated at 70° C. for 4 hrs. The resulting solution wasfiltered, and the solids were washed with DCM. The filtrate fractionswere combined, concentrated in vacuo, and the product was purified byBiotage Isolera. LCMS calculated for C₂₉H₂₆BrN₄O₂ (M+H)⁺: m/z=541.3;Found: 541.3.

Step 2. tert-Butyl(3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclopent-3-en-1-yl)carbamate

3-(6-Bromopyridin-3-yl)-5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine(1.06 g, 2.0 mmol), tert-butyl(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-3-en-1-yl)carbamate(0.73 g, 2.35 mmol), Cs₂CO₃ (1.0 g) and X-Phos Pd G2 (250 mg) in1,4-dioxanes (20 mL) and water (2 mL) were mixed together and flushedwith nitrogen. The mixture was sealed and heated at 80° C. for 3 hr. Thereaction was filtered and the filtrate was concentrated in vacuo. Thecrude material was purified with Biotage Isolera to give the desiredproduct. LCMS calculated for C₃₉H₄₂N₅O₄ (M+H)⁺: m/z=644.3; Found: 644.4.

Step 3. tert-Butyl(3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclopentyl)carbamate

A mixture of tert-butyl(3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclopent-3-en-1-yl)carbamate(1.2 g, 1.86 mmol) and Pd/C (0.30 g) in a solution of methanol (20 mL)and 1,4-dioxanes (20 mL) was stirred under 50 psi of hydrogen overnight.It was then filtered and concentrated in vacuo. The crude material waspurified with Biotage Isolera to give the desired product. LCMScalculated for C₃₉H₄₄N₅O₄ (M+H)⁺: m/z=646.3; Found: 646.4.

Step 4.3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-N-methylcyclopentan-1-amine

2 M solution of LAH in THF (2 ml) was slowly added to a solution oftert-butyl(3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclopentyl)carbamate(0.70 g, 1.084 mmol) in THF (5 ml) upon cooling in the dry ice-hexanebath. The reaction mixture was allowed to warm to r.t. and stirredovernight. The reaction was carefully quenched with ice. To it was added20 mL of 1N NaOH solution. The product was extracted with DCM 2×20 mL.Organic phase was separated, filtered through Celite, dried over Na₂SO₄and concentrated in vacuo. The resulting material was used for next stepwithout further purification. LCMS calculated for C₃₅H₃₈N₅O₂ (M+H)⁺:m/z=560.3; Found: 560.4.

Step 5.N-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclopentyl)-N-methylmethanesulfonamide

Methanesulfonyl chloride (8 mg, 0.071 mmol) was added to a solution of3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-N-methylcyclopentan-1-amine(4 mg, 7.2 μmol) and DIPEA (50 mg) in THF (0.5 mL), and the reactionmixture was stirred at r.t. for 1 h. To this solution 0.5 ml of triflicacid/DCM (1:1) mixture was added and the reaction was stirred at r.t.for additional 1 h. Then the mixture was neutralized with saturatedNaHCO₃ solution and the product was extracted with DCM. The organicphase was washed with brine, dried over sodium sulfate and concentratedin vacuo. The mixture was diluted with CH₃CN and purified by prep-LCMS(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated forC₂₈H₃₂N₅O₃S (M+H)⁺: m/z=518.2; Found: 518.3.

Example 155.N-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclopentyl)-2-hydroxy-N-methylacetamide(Peak 1)

Step 1. tert-Butyl(3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclopentyl)(methyl)carbamate

Boc-anhydride (0.20 g) was added to a solution of3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-N-methylcyclopentan-1-amine(0.10 g, 0.18 mmol) and triethylamine (0.5 mL) in dichloromethane (5mL), and the reaction mixture was stirred at r.t. overnight. Water wasadded to the reaction mixture, and the desired product was extractedwith DCM. Organic phases were combined, dried over sodium sulfate,concentrated in vacuo, and purified by Biotage Isolera. LCMS calculatedfor C₄₀H₄₆N₅O₄ (M+H)⁺: m/z=660.3; Found: 660.4.

The two enantiomers were separated on chiral prep-SFC with chiral columnPhenomenex Lux Sum i-Amylose-1 (21.2×250 mm), eluting with 25% methanolin CO₂ (65 ml/min).

Step 2.3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-N-methylcyclopentan-1-amine(Peak 1)

2 mL of 4N HCl solution in dioxane was added to a solution of tert-butyl(3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclopentyl)(methyl)carbamate(10 mg, 0.015 mmol) (Peak 1 from chiral separation) in 0.5 mL ofmethanol. After the reaction mixture was stirred at r.t. overnight, thesolvent was removed in vacuo, and obtained HCl salt of the desiredproduct was used in the next step without further purification. LCMScalculated for C₃₅H₃₈N₅O₂ (M+H)⁺: m/z=560.3; Found: 560.4.

Step 3.N-(3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclopentyl)-2-hydroxy-N-methylacetamide(Peak 1)

HATU (10 mg) was added to a solution of3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-N-methylcyclopentan-1-amine(5 mg, 8.93 μmol, Peak 1), 2-hydroxyacetic acid (7 mg, 0.089 mmol) andDIPEA (50 mg) DMF (0.5 mL). The reaction mixture was stirred at r.t. for1 h before water was added, and the desired product was extracted withDCM. The organic fractions were combined, dried over sodium sulfate andconcentrated in vacuo.

The residue was dissolved in DCM (2 ml), and trifluoromethanesulfonicacid (0.66 g, 4.4 mmol) was added. The reaction mixture was stirred atr.t for 1 h. Then the mixture was neutralized with saturated NaHCO₃solution and the product was extracted with DCM. The organic phase waswashed with brine, dried over sodium sulfate and concentrated in vacuo.The mixture was diluted with CH₃CN and purified by prep-LCMS (XBridgeC18 column, eluting with a gradient of acetonitrile/water containing0.1% TFA, at flow rate of 60 mL/min). LCMS calculated for C₂₉H₃₂N₅O₃(M+H)⁺: m/z=498.2; Found: 498.3.

Example 156.(2S)—N-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclopentyl)-2-hydroxypropanamid

Step 1.3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclopentan-1-amine

tert-Butyl(3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclopentyl)carbamate(0.10 g, 0.155 mmol) was dissolved in DCM (2 ml), andtrifluoromethanesulfonic acid (0.66 g, 4.4 mmol) was added. The reactionmixture was stirred at r.t for 1 h. Then the mixture was neutralizedwith saturated NaHCO₃ solution and the product was extracted with DCM.The organic phase was washed with brine, dried over sodium sulfate andconcentrated in vacuo. LCMS calculated for C₂₆H₂₈N₅O (M+H)⁺: m/z=426.3;Found: 426.4.

Step 2.(2S)—N-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclopentyl)-2-hydroxypropanamid

HATU (10 mg) was added to a solution of3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclopentan-1-amine(0.005 g, 11.7 mop, (S)-2-hydroxypropanoic acid (8.25 mg, 0.092 mmol)and DIPEA (50 mg) in DMF (0.5 mL), and the reaction mixture was stirredat r.t. for 1 h. The reaction mixture was then diluted with 4.5 mL ofmethanol, filtered and purified by prep-LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min). LCMS calculated for C₂₉H₃₂N₅O₃ (M+H)⁺:m/z=498.2; Found: 498.3.

Example 157.N-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclopentyl)-2-hydroxyacetamide

HATU (10 mg) was added to a solution of3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclopentan-1-amine(5 mg, 11.7 μmol), 2-hydroxyacetic acid (7 mg, 0.092 mmol) and DIPEA (50mg) in DMF (0.5 mL), and the reaction mixture was stirred at r.t. for 1h. The reaction mixture was then diluted with 4.5 mL of methanol,filtered and purified by prep-LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min). LCMS calculated for C₂₈H₃₀N₅O₃ (M+H)⁺: m/z=484.2; Found: 484.4.

Example 158.2-(1-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)phenyl)-3-azabicyclo[3.1.0]hexan-3-yl)ethan-1-ol

Step 1.1-(4-Bromophenyl)-3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-azabicyclo[3.1.0]hexane

To a solution of 1-(4-bromophenyl)-3-azabicyclo[3.1.0]hexane (1.0 g,4.20 mmol) and 2-((tert-butyldimethylsilyl)oxy)acetaldehyde (3.66 g,21.00 mmol) in DCM (42.0 ml) was added sodium triacetoxyhydroborate(2.67 g, 12.60 mmol), and the resulting mixture was stirred at r.t. for20 hrs. After this time, the solution was diluted with water and theproduct was extracted with DCM. The combined organic phases were washedwith sat. aq. NaCl and dried with Na₂SO₄, then filtered and concentratedto dryness. The residue was then purified by silica gel chromatographyto afford the desired product. LC-MS calculated for C₁₉H₃₁BrNOSi (M+H)⁺:m/z=396.1; found 396.3.

Step 2.3-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-azabicyclo[3.1.0]hexane

A mixture of1-(4-bromophenyl)-3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-azabicyclo[3.1.0]hexane(1.62 g, 4.09 mmol), bis(pinacolato)diboron (1.45 g, 5.72 mmol),PdCl₂dppf*DCM (0.501 g, 0.613 mmol) and potassium acetate (1.2 g, 12.26mmol) in dioxane (30 ml) was heated to 85° C. for 20 hrs. The reactionmixture was then filtered through Celite, washed with EtOAc, andconcentrated. The residue was then purified by silica gel chromatographyto afford the desired product. LCMS calculated for C₂₅H₄₃BNO₃Si (M+H)⁺:m/z=444.3; Found: 444.5.

Step 3.2-(1-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)phenyl)-3-azabicyclo[3.1.0]hexan-3-yl)ethan-1-ol

A mixture of tert-butyl5-(2,3-dihydro-1H-inden-4-yl)-3-iodo-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate(30 mg, 0.061 mmol),3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-azabicyclo[3.1.0]hexane(54 mg, 0.122 mmol), Xphos Pd G2 (10 mg, 0.012 mmol), and potassiumphosphate (39 mg, 0.183 mmol) in dioxane (1 ml) and water (0.1 ml) washeated to 80° C. for 20 hrs. After this time, the solution was cooled tor.t., diluted with water and extracted with EtOAc. The combined organicphases were washed with sat. aq. NaCl and dried over Na₂SO₄, thenfiltered and concentrated to dryness. The residue was then dissolved inDCM (1 mL) and TFA (1 mL) was added. The mixture was stirred at r.t. for1 h and purified by prep-LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min). LCMS calculated for C₂₉H₃₁N₄O₂ (M+H)⁺: m/z=467.2; found 467.3.

Example 159.4-(3-(4-((1R,5S)-3-(2-Hydroxyethyl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile

Step 1.(1R,5S)-3-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-azabicyclo[3.1.0]hexane

This compound was prepared according to the procedure described inExample 158, using (1R,5S)-1-(4-bromophenyl)-3-azabicyclo[3.1.0]hexaneinstead of 1-(4-bromophenyl)-3-azabicyclo[3.1.0]hexane. LCMS calculatedfor C₂₅H₄₃BNO₃Si (M+H)⁺: m/z=444.3; Found: 444.5.

Step 2.4-(3-(4-((1R,5S)-3-(2-Hydroxyethyl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile

This compound was prepared according to the procedure described inExample 158, using 4-(3-iodo-6-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrileand(1R,5S)-3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-azabicyclo[3.1.0]hexaneinstead of tert-butyl5-(2,3-dihydro-1H-inden-4-yl)-3-iodo-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylateand 3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-azabicyclo[3.1.0]hexaneas starting materials. LCMS calculated for C₃₀H₃₀N₅O₂ (M+H)⁺: m/z=492.2;Found: 492.4.

Example 160.1-((5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)methyl)piperidin-4-ol

Step 1. tert-Butyl5-(2,3-dihydro-1H-inden-4-yl)-3-(6-(hydroxymethyl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate

A mixture of tert-butyl5-(2,3-dihydro-1H-inden-4-yl)-3-iodo-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate(1.5 g, 3.05 mmol),(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)methanol(1.8 g, 7.63 mmol), XPhos Pd G2 (0.48 g, 0.61 mmol), and potassiumphosphate (2.59 g, 12.21 mmol) in dioxane (20 ml) and water (2.0 ml) washeated to 80° C. for 20 hrs. After this time, the solution was cooled tor.t., diluted with water and the product was extracted with EtOAc. Thecombined organic phases were washed with sat. aq. NaCl and dried withNa₂SO₄, then filtered and concentrated to dryness. The residue was thenpurified by silica gel chromatography to afford the desired product.LCMS calculated for C₂₇H₂₉N₄O₄ (M+H)⁺: m/z=473.2; Found: 473.1.

Step 2. tert-Butyl5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-3-(6-(((methylsulfonyl)oxy)methyl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine-1-carboxylate

To a solution of tert-butyl5-(2,3-dihydro-1H-inden-4-yl)-3-(6-(hydroxymethyl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate(400 mg, 0.846 mmol) and N,N-diisopropylethylamine (591 μl, 3.39 mmol)in DCM (10 ml) was added methanesulfonyl chloride (200 μl, 2.54 mmol).The resulting solution was stirred at r.t. for 1.5 hrs. The reaction wasthen quenched with sat. aq. NaHCO₃, extracted with DCM, dried overNa₂SO₄ and concentrated. The crude product was used directly in the nextstep. LCMS calculated for C₂₈H₃₁N₄O₆S (M+H)⁺: m/z=551.2; Found: 551.0.

Step 3.1-((5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)methyl)piperidin-4-ol

A mixture of tert-butyl5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-3-(6-(((methylsulfonyl)oxy)methyl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine-1-carboxylate(30 mg, 0.054 mmol), piperidin-4-ol (11 mg, 0.109 mmol), and potassiumcarbonate (23 mg, 0.163 mmol) in DMF (0.5 ml) was heated to 50° C. for 2hrs. After this time, the solution was cooled to r.t., diluted withwater and extracted with DCM. The combined organic phases were washedwith sat. aq. NaCl and dried with Na₂SO₄, then filtered and concentratedto dryness. The residue was then dissolved in DCM (1 mL), and TFA (1 mL)was added. The mixture was stirred at r.t. for 1 h and purified byprep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₂₇H₃₀N₅O₂ (M+H)⁺: m/z=456.2; found 456.2.

Example 161.5-((5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)methyl)-2-oxa-5-azabicyclo[2.2.1]heptane

This compound was prepared according to the procedure described inExample 160, using 2-oxa-5-azabicyclo[2.2.1]heptane hydrochlorideinstead of piperidin-4-ol. LC-MS calculated for C₂₇H₂₈N₅O₂ (M+H)⁺:m/z=454.2; found 454.1.

Example 162.4-(1-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)ethyl)morpholine

Step 1. tert-Butyl3-(6-acetylpyridin-3-yl)-5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate

A mixture of tert-butyl5-(2,3-dihydro-1H-inden-4-yl)-3-iodo-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate(0.30 g, 0.611 mmol),1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)ethan-1-one(0.27 g, 1.093 mmol), SPhos Pd G3 (0.095 g, 0.122 mmol), and cesiumcarbonate (0.6 g, 1.832 mmol) in dioxane (4 ml) and water (0.4 ml) washeated at 80° C. for 2 hrs. After this time, the solution was cooled tor.t., diluted with water and extracted with EtOAc. The combined organicphases were washed with sat. aq. NaCl and dried with Na₂SO₄, thenfiltered and concentrated to dryness. The residue was then purified bysilica gel chromatography to afford the desired product. LCMS calculatedfor C₂₈H₂₉N₄O₄ (M+H)⁺: m/z=485.2; Found: 485.0.

Step 2.4-(1-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)ethyl)morpholine

A mixture of tert-butyl3-(6-acetylpyridin-3-yl)-5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate(30 mg, 0.062 mmol), morpholine (11 mg, 0.124 mmol), and sodiumtriacetoxyhydroborate (26 mg, 0.124 mmol) in DCM (1 ml) was stirred atr.t. for 20 hrs. After this time, the solution was diluted with waterand extracted with DCM. The combined organic phases were washed withsat. aq. NaCl and dried with Na₂SO₄, then filtered and concentrated todryness. The residue was then dissolved in DCM (1 mL), and TFA (1 mL)was added. The mixture was stirred at r.t. for 1 h and purified byprep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₂₇H₃₀N₅O₂ (M+H)⁺: m/z=456.2; found 456.2.

Example 163.7-((5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine

This compound was prepared according to the procedure described inExample 160, using 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazineinstead of piperidin-4-ol. LC-MS calculated for C₂₇H₂₇N₈O (M+H)⁺:m/z=479.2; found 479.0.

Example 164.4-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-1-(2-hydroxyethyl)piperidine-4-carbonitrile

Step 1. tert-Butyl4-(5-bromopyridin-2-yl)-4-cyanopiperidine-1-carboxylate

To a solution of tert-butyl 4-cyanopiperidine-1-carboxylate (2.0 g, 9.51mmol) in THF (48 ml) at 0° C. was added a solution of sodiumbis(trimethylsilyl)amide in THF (1.0 M, 12.4 mL, 12.4 mmol) dropwise.The resulting solution was stirred at r.t. After 1 hr,5-bromo-2-fluoropyridine (2.5 g, 14.27 mmol) was added dropwise and theresulting solution was stirred at r.t. for 20 hrs. After this time, thesolution was quenched with water and extracted with DCM. The combinedorganic phases were washed with sat. aq. NaCl and dried with Na₂SO₄,then filtered and concentrated to dryness. The residue was then purifiedby silica gel chromatography to afford the desired product. LCMScalculated for C₁₂H₁₃BrN₃O₂ (M-C4H₇)⁺: m/z=310.0; Found: 309.9.

Step 2. tert-Butyl4-cyano-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperidine-1-carboxylate

A mixture of tert-butyl4-(5-bromopyridin-2-yl)-4-cyanopiperidine-1-carboxylate (2.50 g, 6.83mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.4g, 9.6 mmol), PdCl₂dppf.DCM (0.836 g, 1.02 mmol), and potassium acetate(2.01 g, 20.5 mmol) in dioxane (50 ml) was heated at 85° C. for 20 hrs.The reaction mixture was then filtered through celite, washed withEtOAc, and concentrated. The residue was then purified by silica gelchromatography to afford the desired product. LCMS calculated forC₁₈H₂₅BN₃O₄ (M-C4H₇)⁺: m/z=358.2; Found: 358.1.

Step 3.4-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidine-4-carbonitrile

A mixture of tert-butyl5-(2,3-dihydro-1H-inden-4-yl)-3-iodo-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate(265 mg, 0.539 mmol), tert-butyl4-cyano-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperidine-1-carboxylate(446 mg, 1.08 mmol), SPhos Pd G3 (84 mg, 0.108 mmol), and cesiumcarbonate (527 mg, 1.618 mmol) in dioxane (3 ml) and water (0.3 ml) washeated to 80° C. for 20 hrs. After this time, the solution was cooled tor.t., diluted with water and extracted with EtOAc. The combined organicphases were washed with sat. aq. NaCl and dried with Na₂SO₄, thenfiltered and concentrated to dryness. The residue was then dissolved inDCM (3 mL), and TFA (2 mL) was added. The solution was stirred at r.t.for 1 h. The solvent was then removed and the residue was purified bysilica gel chromatography to afford the desired product. LCMS calculatedfor C₂₇H₂₇N₆O (M+H)⁺: m/z=451.2; Found: 451.2.

Step 4.4-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-1-(2-hydroxyethyl)piperidine-4-carbonitrile

A mixture of4-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidine-4-carbonitrile(30 mg, 0.067 mmol), 2-((tert-butyldimethylsilyl)oxy)acetaldehyde (35mg, 0.200 mmol), and sodium triacetoxyhydroborate (28 mg, 0.133 mmol) inDCM (1 ml) was stirred at r.t. for 20 hrs. After this time, the solutionwas diluted with water and extracted with DCM. The combined organicphases were washed with sat. aq. NaCl and dried with Na₂SO₄, thenfiltered and concentrated to dryness. The residue was then dissolved inDCM (1 mL), and TFA (1 mL) was added. The mixture was stirred at r.t.for 1 h and purified by prep-LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min). LCMS calculated for C₂₉H₃₁N₆O₂ (M+H)⁺: m/z=495.2; found 495.0.

Example 165.4-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-1-(2-hydroxyacetyl)piperidine-4-carbonitrile

A mixture of4-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidine-4-carbonitrile(30 mg, 0.067 mmol), 2-hydroxyacetic acid (5 mg, 0.067 mmol), HATU (38mg, 0.10 mmol), and N,N-diisopropylethylamine (23 μl, 0.133 mmol) in DMF(0.5 ml) was stirred at r.t. for 1 hr. The mixture was then diluted withMeCN and purified by prep-LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min). LCMS calculated for C₂₉H₂₉N₆O₃ (M+H)⁺: m/z=509.2; found 509.0.

Example 166.2-(3-(6-Methoxy-3-(6-(4-(2-methoxyethyl)piperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2-methylphenyl)acetonitrile

Step 1.1-(2-Methoxyethyl)-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine

This compound was prepared according to the procedures described inExample 89, step 1, using 1-bromo-2-methoxyethane instead of2-bromoethan-1-ol as starting material. The product was isolated as theTFA salt. LCMS calculated for C₁₂H₂₁BN₃O₃ (Boronic acid, M+H)⁺:m/z=266.2, found: 266.3.

Step 2.2-(3-(6-Methoxy-3-(6-(4-(2-methoxyethyl)piperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2-methylphenyl)acetonitrile

This compound was prepared according to the procedures described inExample 89, step 2, using1-(2-methoxyethyl)-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazineinstead of2-(4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazin-1-yl)ethan-1-olas starting material. The mixture was purified by prep-LCMS (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%TFA, at flow rate of 60 mL/min). The product was isolated as the TFAsalt. LC-MS calculated for C₂₈H₃₂N₇O₂ (M+H)⁺: m/z=498.3, found 498.4. ¹HNMR (500 MHz, DMSO-d6) δ 13.40-12.90 (s, 1H), 9.89-9.71 (s, 1H), 8.48(d, J=9.0 Hz, 1H), 7.54 (s, 1H), 7.45 (d, J=7.5 Hz, 1H), 7.35 7.30 (m,1H), 7.28 (d, J=7.6 Hz, 1H), 7.08 (d, J=8.9 Hz, 1H), 4.42 (d, J=14.0 Hz,2H), 4.09 (s, 2H), 3.84 (s, 3H), 3.69 (t, J=4.9 Hz, 2H), 3.57 (d, J=12.1Hz, 2H), 3.39-3.32 (m, 5H), 3.25 (t, J=13.0 Hz, 2H), 3.17-3.07 (m, 2H),2.05 (s, 3H) ppm.

Example 167.4-(6-Methoxy-3-(1-(1-(tetrahydro-2H-pyran-4-carbonyl)piperidin-4-yl-4-d)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile

Step 1. tert-Butyl 4-hydroxypiperidine-1-carboxylate-4-d

To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (2.0 g, 10mmol) in methanol (20 mL) at 0° C. was added sodium borodeuteride (0.84g, 20 mmol) portionwise. After addition was completed, the reactionmixture was stirred under nitrogen at 0° C. for 2 hrs. The reactionmixture was then allowed to warm to room temperature for 45 minutes,before quenching with brine. The aqueous solution was extracted 3 timeswith ethyl acetate. The pooled organic extracts were dried over sodiumsulfate, filtered, and the solvent was removed in vacuo. The resultantproduct was used in the next step without further purification. LCMScalculated for C₆H₁₁DNO₃ (M-tBu+H)⁺: m/z=147.1, found: 147.1.

Step 2. tert-Butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate-4-d

To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate-4-d (2.1g, 10 mmol) in anhydrous dichloromethane (103 mL) at 0° C. was addedtriethylamine (2.2 g, 15 mmol) by syringe. Dropwise by syringe,methanesulfonyl chloride (0.97 mL, 12 mmol) was added to the stirredreaction mixture. The reaction was allowed to warm to room temperaturefor 1 hr before the solvent was removed in vacuo. The resultant residuewas dissolved in 100 mL of diethyl ether. The ether solution wassequentially washed with 15 mL 1 M aqueous hydrochloric acid, 15 mLwater, and 15 mL saturated aqueous sodium bicarbonate. The organic phasewas then dried over sodium sulfate, filtered, and the solvent wasremoved in vacuo. The resultant product was used in the next stepwithout further purification. LCMS calculated for C₇H₁₃DNO₅S (M-tBu+H)⁺:m/z=225.1, found: 225.0.

Step 3. tert-Butyl4-(4-iodo-1H-pyrazol-1-yl)piperidine-1-carboxylate-4-d

To a solution of 4-iodo-1H-pyrazole (1.46 g, 7.54 mmol) in DMF (26 mL)at 0° C. was added sodium hydride (0.362 g, 60 wt %, 9.04 mmol)portionwise. After addition was completed, the reaction mixture wasstirred under nitrogen at 0° C. for 1 hr. Then, to this solution wasadded tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate-4-d(2.32 g, 8.29 mmol) in DMF (3 mL). The reaction mixture was then heatedto 100° C. for 3 hrs, after which it was cooled back to room temperatureand quenched with 50 mL water. The aqueous solution was extracted 4times with 50 mL ethyl acetate. The pooled organic phases were thendried over sodium sulfate, filtered, and the solvent was removed invacuo. The residue was purified by silica gel chromatography to affordthe desired product. LCMS calculated for C₉H₁₂DIN₃O₂ (M-tBu+H)⁺:m/z=323.0, found: 323.0.

Step 4. tert-Butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate-4-d

To a solution of tert-butyl4-(4-iodo-1H-pyrazol-1-yl)piperidine-1-carboxylate-4-d (1.95 g, 5.15mmol) in DMSO (22 ml) were added bis(pinacolato)diboron (1.83 g, 7.21mmol), potassium acetate (2.02 g, 20.6 mmol), andtetrakis(triphenylphosphine)palladium(0) (595 mg, 0.515 mmol). Thereaction was purged with N₂ and stirred at 80° C. for 2 hrs. After thistime it was cooled to room temperature and filtered through a pad ofCelite, rinsing with ethyl acetate. The organic solution was then washedtwice with brine, dried over sodium sulfate, filtered, and concentratedin vacuo. The residue was purified by silica gel chromatography toafford the desired product. LCMS calculated for C₁₉H₃₂DBN₃O₄ (M+H)⁺:m/z=379.3, found: 379.3.

Step 5. tert-Butyl3-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl-4-d)-1H-pyrazol-4-yl)-5-(1-cyano-2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate

To a solution of tert-butyl5-(1-cyano-2,3-dihydro-1H-inden-4-yl)-3-iodo-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate(Example 75, step 7; 287 mg, 0.555 mmol) in 1,4-dioxane (4.6 mL) andwater (0.93 mL) was added tert-butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate-4-d(252 mg, 0.666 mmol), potassium phosphate (236 mg, 1.11 mmol), andXphosPd G2 (44 mg, 0.055 mmol). The reaction was degassed with N₂ andstirred at 60° C. for 2 hr. After this time it was cooled to roomtemperature and filtered through a pad of Celite, rinsing with ethylacetate. The residue was purified by silica gel chromatography to affordthe desired product. LCMS calculated for C₃₅H₄₁DN₇O₅ (M+H)⁺: m/z=641.3,found: 641.4.

Step 6.4-(6-Methoxy-3-(1-(piperidin-4-yl-4-d)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile

To a solution of tert-butyl3-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl-4-d)-1H-pyrazol-4-yl)-5-(1-cyano-2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate(15 mg, 0.023 mmol) in dichloromethane (82 μL) was added TFA (82 μL, 1.1mmol) at room temperature. The reaction mixture was stirred for 30 min,then concentrated in vacuo.

The residue was adjusted to pH 7 by addition of saturated aqueous sodiumbicarbonate, then extracted twice with 10% methanol/dichloromethane. Thepooled organic extracts were dried over sodium sulfate, filtered, andconcentrated in vacuo. The resultant product was used in next stepwithout further purification. LCMS calculated for C₂₅H₂₅DN₇O (M+H)⁺:m/z=441.2, found: 441.2.

Step 7.4-(6-Methoxy-3-(1-(1-(tetrahydro-2H-pyran-4-carbonyl)piperidin-4-yl-4-d)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile

To a solution of4-(6-methoxy-3-(1-(piperidin-4-yl-4-d)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile(10 mg, 0.023 mmol), tetrahydro-2H-pyran-4-carboxylic acid (3.0 mg,0.023 mmol), and BOP (15 mg, 0.035 mmol) in DMF (0.36 mL) was addeddiisopropylethylamine (10 μL, 0.058 mmol) with stirring at roomtemperature. Stirring of the reaction mixture was continued for 80 min,then it was diluted with MeOH and purified by prep-LCMS (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%TFA, at flow rate of 60 mL/min). The product was isolated as the TFAsalt. LC-MS calculated for C₃₁H₃₃DN₇O₃ (M+H)⁺: m/z=553.3, found 553.3.

Example 168.4-(6-Methoxy-3-(1-((S)-1-(2-methoxyacetyl)pyrrolidin-3-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile

Step 1. tert-Butyl3-(1-((S)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-1H-pyrazol-4-yl)-5-(1-cyano-2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate

This compound was prepared according to the procedures described inExample 167, step 5, using tert-butyl(S)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylateinstead of tert-butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate-4-das starting material. The residue was purified by silica gelchromatography to afford the desired product. Separation ofdiastereomers was achieved by chiral prep-SFC (ChiralPak IH Sum 21.2×250mm, eluting with 15% EtOH (containing 2 mM ammonia), at 40° C., at aflow rate of 70 mL/min, t_(R, peak 1)=4.6 min t_(R, peak 2)=5.8 min).Peak 2 was collected and the solvents were evaporated in vacuo. LCMScalculated for C₃₀H₃₂N₇O₅ (M-tBu+H)⁺: m/z=570.3, found: 570.3.

Step 2.4-(6-Methoxy-3-(1-((S)-pyrrolidin-3-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile

This compound was prepared according to the procedures described inExample 167, step 6, using tert-butyl3-(1-((S)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-1H-pyrazol-4-yl)-5-(1-cyano-2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylateinstead of tert-butyl3-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl-4-d)-1H-pyrazol-4-yl)-5-(1-cyano-2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylateas starting material. LCMS calculated for C₂₄H₂₄N₇O (M+H)⁺: m/z=426.2,found: 426.2.

Step 3.4-(6-Methoxy-3-(1-((S)-1-(2-methoxyacetyl)pyrrolidin-3-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile

This compound was prepared according to the procedures described inExample 167, step 7, using4-(6-methoxy-3-(1-((S)-pyrrolidin-3-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrileinstead of4-(6-methoxy-3-(1-(piperidin-4-yl-4-d)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrileand using 2-methoxyacetic acid instead oftetrahydro-2H-pyran-4-carboxylic acid as starting materials. LCMScalculated for C₂₇H₂₈N₇O₃ (M+H)⁺: m/z=498.2, found: 498.2.

Example 169.4-(6-Methoxy-3-(1-((S)-1-((S)-tetrahydrofuran-2-carbonyl)pyrrolidin-3-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile

This compound was prepared according to the procedures described inExample 167, step 7, using4-(6-methoxy-3-(1-((S)-pyrrolidin-3-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrileinstead of4-(6-methoxy-3-(1-(piperidin-4-yl-4-d)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrileand using (S)-tetrahydrofuran-2-carboxylic acid instead oftetrahydro-2H-pyran-4-carboxylic acid as starting materials. LCMScalculated for C₂₉H₃₀N₇O₃ (M+H)⁺: m/z=524.2, found: 524.2.

Example 170.(7R,8aS)-2-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol

This compound was prepared according to the procedures described inExample 90, using2-(2,3-dihydro-1H-inden-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneinstead of (3-methoxy-2-methylphenyl)boronic acid as starting material.The product was isolated as the TFA salt. LCMS calculated for C₂₈H₃₁N₆O₂(M+H)⁺: m/z=483.3; Found: 483.3.

Example 171.N-(1-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-3-yl)-2-hydroxy-N-methylacetamide

Step 1. tert-Butyl(1-(5-bromopyridin-2-yl)azetidin-3-yl)(methyl)carbamate

To a solution of 5-bromo-2-fluoropyridine (2 g, 11.36 mmol) in DMSO (10mL) was added tert-butyl azetidin-3-yl(methyl)carbamate (2.18 g, 11.36mmol) and cesium carbonate (7.4 g, 22.73 mmol). The reaction wasdegassed with N₂ and stirred at 100° C. for 2 hrs. After this time, itwas cooled to r.t. and diluted with EtOAc. The resultant solution waswashed sequentially with water, sat. aq. NaCl solution, and dried overNa₂SO₄. The organic phases were filtered and concentrated to dryness.The residue was purified by Biotage Isolera to afford the desiredproduct. LC-MS calculated for C₁₄H₂₁BrN₃O₂ (M+H)⁺: m/z=342.1; found342.1.

Step 2. tert-Butylmethyl(1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)azetidin-3-yl)carbamate

A mixture of tert-butyl(1-(5-bromopyridin-2-yl)azetidin-3-yl)(methyl)carbamate (2.96 g, 8.65mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (3.3g, 12.97 mmol),[1,1′-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II) (706 mg,0.865 mmol) and potassium acetate (1.66 g, 17.3 mmol) in dioxane (20 mL)was stirred at 100° C. for 90 minutes. After cooling to r.t., thereaction mixture was filtered, the solvent was evaporated in vacuo andthe crude material was purified by Biotage Isolera. LCMS calculated forC₂₀H₃₃BN₃O₄ (M+H)⁺: m/z=390.2; Found: 390.2.

Step 3. tert-Butyl(1-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-3-yl)(methyl)carbamate

To a solution of5-(2,3-dihydro-1H-inden-4-yl)-3-iodo-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine(Example 53, step 3; 1 g, 1.96 mmol) in 1,4-dioxane (6 mL) and water(1.2 mL) was added tert-butylmethyl(1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)azetidin-3-yl)carbamate(1.14 g, 2.93 mmol), potassium phosphate (1.25 g, 5.87 mmol), and[1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (160 mg,0.196 mmol). The reaction was degassed with N₂ and stirred at 80° C. for2 hrs. After this time, it was cooled to r.t. and diluted with EtOAc.The resultant solution was washed sequentially with water, sat. aq. NaClsolution, and dried over Na₂SO₄. The organic phases were filtered andconcentrated to dryness. The residue was purified by Biotage Isolera toafford the desired product. LC-MS calculated for C₃₈H₄₃N₆O₄ (M+H)⁺:m/z=647.3; found 647.3.

Step 4.1-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-N-methylazetidin-3-amine

To a solution of tert-butyl(1-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-3-yl)(methyl)carbamate(1.01 g, 1.56 mmol) in dichloromethane (3 mL) was added trifluoroaceticacid (4 mL). The reaction was stirred at r.t. for 1 hr. After this time,it was diluted with dichloromethane. The resultant solution was washedsequentially with water, sat. aq. NaCl solution and dried over Na₂SO₄.The organic phases were filtered and concentrated to dryness. Theresidue was used directly in the next step without purification. LC-MScalculated for C₃₃H₃₅N₆O₂ (M+H)⁺: m/z=547.3; found 547.3.

Step 5.N-(1-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-3-yl)-2-hydroxy-N-methylacetamide

To a solution of1-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-N-methylazetidin-3-amine(200 mg, 0.37 mmol) in dichloromethane (4 mL) was added 2-hydroxyaceticacid (42 mg, 0.55 mmol), trimethylamine (95 mg, 0.73 mmol) and HATU (181mg, 0.48 mmol). The reaction was stirred at r.t. for 1 hr. After thistime, it was diluted with dichloromethane. The resultant solution waswashed sequentially with water, sat. aq. NaCl solution, and dried overNa₂SO₄. The organic phases were filtered and concentrated to dryness.The residue was dissolved in dichloromethane (3 mL) andtrifluoromethanesulfonic acid (1.5 mL). The reaction was stirred at r.t.After 30 min, the reaction mixture was quenched with 4N NaOH aq.solution and diluted with dichloromethane. The resultant mixture waswashed sequentially with water, sat. aq. NaCl solution and dried overNa₂SO₄. The organic phases were filtered and concentrated to dryness.The residue was diluted with MeOH and was purified by prep-LCMS (XBridgeC18 column, eluting with a gradient of acetonitrile/water containing0.1% TFA, at flow rate of 60 mL/min). The product was isolated as theTFA salt. LC-MS calculated for C₂₇H₂₉N₆O₃ (M+H)⁺: m/z=485.2; found485.2.

Example 172.(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-1-yl)(tetrahydrofuran-2-yl)methanone

Step 1. tert-Butyl 3-(5-bromopyridin-2-yl)azetidine-1-carboxylate

To a solution of zinc dust (1.73 g, 26.5 mmol) in THF (30 mL) was added1,2-dibromoethane (332 mg, 1.77 mmol) and chlorotrimethylsilane (192 mg,1.77 mmol). The reaction was degassed with N₂ and stirred at 60° C. for15 minutes before tert-butyl 3-iodoazetidine-1-carboxylate (5 g, 17.7mmol) in DMA (30 mL) was added. The mixture was heated to 60° C. andstirred for 15 minutes before cooled down to r.t. To the cooled mixturewas added 2,5-dibromopyridine (4.6 g, 19.4 mmol),[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (1:1) (721mg, 0.88 mmol) and copper iodide (168 mg, 0.88 mmol). The mixture washeated to 80° C. for 2 hrs. After this time, it was cooled to r.t. anddiluted with EtOAc. The resultant solution was washed sequentially withwater, sat. aq. NaCl solution, and dried over Na₂SO₄. The organic phaseswere filtered and concentrated to dryness. The residue was purified byBiotage Isolera to afford the desired product. LC-MS calculated forC₁₃H₁₈BrN₂O₂ (M+H)⁺: m/z=313.0; found 313.0.

Step 2. tert-Butylmethyl(1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)azetidin-3-yl)carbamate

A mixture of tert-butyl(1-(5-bromopyridin-2-yl)azetidin-3-yl)(methyl)carbamate (2.96 g, 8.65mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (3.3g, 12.97 mmol),[1,1′-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II) (706 mg,0.865 mmol) and potassium acetate (1.66 g, 17.3 mmol) in dioxane (20 mL)was stirred at 100° C. for 90 minutes. After cooling to r.t., thereaction mixture was filtered, the solvent was evaporated in vacuo andthe crude material was purified by Biotage Isolera. LCMS calculated forC₂₀H33BN₃O₄ (M+H)⁺: m/z=390.2; Found: 390.2.

Step 3. tert-Butyl3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidine-1-carboxylate

To a solution of5-(2,3-dihydro-1H-inden-4-yl)-3-iodo-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine(Example 53, step 3; 545 mg, 1.07 mmol) in 1,4-dioxane (5 mL) and water(1 mL) was added tert-butyl3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)azetidine-1-carboxylate(499 mg, 1.39 mmol), potassium phosphate (521 mg, 1.60 mmol), and(2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (83 mg, 0.11mmol). The reaction was degassed with N₂ and stirred at 80° C. for 2hrs. After this time, it was cooled to r.t. and diluted with EtOAc. Theresultant solution was washed sequentially with water, sat. aq. NaClsolution, and dried over Na₂SO₄. The organic phases were filtered andconcentrated to dryness. The residue was purified by Biotage Isolera toafford the desired product. LC-MS calculated for C₃₇H₄₀N₅O₄ (M+H)⁺:m/z=618.3; found 618.3.

Step 4.3-(6-(Azetidin-3-yl)pyridin-3-yl)-5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine

To a solution of tert-butyl3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidine-1-carboxylate(527 mg, 0.85 mmol) in dichloromethane (2 mL) was added trifluoroaceticacid (2 mL). The reaction was stirred at r.t. for 1 hr. After this time,it was diluted with dichloromethane. The resultant solution was washedsequentially with water, sat. aq. NaCl solution and dried over Na₂SO₄.The organic phases were filtered and concentrated to dryness. Theresidue was used directly in the next step without purification. LC-MScalculated for C₃₂H₃₂N₅O₂ (M+H)⁺: m/z=518.2; found 518.2.

Step 5.(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-1-yl)(tetrahydrofuran-2-yl)methanone

To a solution of3-(6-(azetidin-3-yl)pyridin-3-yl)-5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine(20 mg, 0.039 mmol) in dichloromethane (0.5 mL) was addedtetrahydrofuran-2-carboxylic acid (9 mg, 0.077 mmol), triethylamine (10mg, 0.077 mmol) and HATU (22 mg, 0.058 mmol). The reaction was stirredat r.t. for 1 hr. After this time, it was diluted with dichloromethane.The resultant solution was washed sequentially with water, sat. aq. NaClsolution, and dried over Na₂SO₄. The organic phases were filtered andconcentrated to dryness. The residue was dissolved in dichloromethane(0.5 mL) and trifluoromethanesulfonic acid (0.1 mL). The reaction wasstirred at r.t. After 30 min, the reaction mixture was quenched with 4NNaOH aq. solution and diluted with dichloromethane. The resultantmixture was washed sequentially with water, sat. aq. NaCl solution anddried over Na₂SO₄. The organic phases were filtered and concentrated todryness. The residue was diluted with MeOH and was purified by prep-LCMS(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% TFA, at flow rate of 60 mL/min). The product wasisolated as the TFA salt. LC-MS calculated for C₂₉H₃₀N₅O₃ (M+H)⁺:m/z=496.2; found 496.2.

Example 173.(S)-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-1-yl)(1-methylpiperidin-2-yl)methanone

This compound was prepared according to the procedures described inExample 172, step 5, using (S)-1-methylpiperidine-2-carboxylic acidinstead of tetrahydrofuran-2-carboxylic acid as starting material. Theproduct was isolated as the TFA salt. LCMS calculated for C₃₁H₃₅N₆O₂(M+H)⁺: m/z=523.3; Found: 523.3.

Example 174.1-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-1-yl)-2-(dimethylamino)ethan-1-one

This compound was prepared according to the procedures described inExample 172, step 5, using dimethylglycine instead oftetrahydrofuran-2-carboxylic acid as starting material. The product wasisolated as the TFA salt. LCMS calculated for C₂₈H₃₁N₆O₂ (M+H)⁺:m/z=483.2; Found: 483.2.

Example 175.1-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-1-yl)-3-hydroxypropan-1-one

This compound was prepared according to the procedures described inExample 172, step 5, using 3-hydroxypropanoic acid instead oftetrahydrofuran-2-carboxylic acid as starting material. The product wasisolated as the TFA salt. LCMS calculated for C₂₇H₂₈N₅O₃ (M+H)⁺:m/z=470.2; Found: 470.2.

Example 176.1-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-1-yl)-2-hydroxyethan-1-one

This compound was prepared according to the procedures described inExample 172, step 5, using 2-hydroxyacetic acid instead oftetrahydrofuran-2-carboxylic acid as starting material. The product wasisolated as the TFA salt. LCMS calculated for C₂₆H₂₆N₅O₃ (M+H)⁺:m/z=456.2; Found: 456.2.

Example 177.(S)-1-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-1-yl)-2-hydroxypropan-1-one

This compound was prepared according to the procedures described inExample 172, step 5, using (S)-2-hydroxypropanoic acid instead oftetrahydrofuran-2-carboxylic acid as starting material. The product wasisolated as the TFA salt. LCMS calculated for C₂₇H₂₈N₅O₃ (M+H)⁺:m/z=470.2; Found: 470.2.

Example 178.N-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclobutyl)-2-hydroxy-N-methylacetamide

Step 1. tert-Butyl (3-(5-bromopyridin-2-yl)cyclobutyl)(methyl)carbamate

To a solution of zinc dust (892 mg, 13.64 mmol) in THF (20 mL) was added1,2-dibromoethane (171 mg, 0.91 mmol) and chlorotrimethylsilane (99 mg,0.91 mmol). The reaction was degassed with N₂ and stirred at 60° C. for15 minutes before tert-butyl (3-iodocyclobutyl)(methyl)carbamate (2.83g, 9.09 mmol) in DMA (20 mL) was added. The mixture was heated to 60° C.and stirred for 15 minutes before cooled down to r.t. To the cooledmixture was added 2,5-dibromopyridine (2.37 g, 10 mmol),[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (1:1) (371mg, 0.46 mmol) and copper iodide (87 mg, 0.049 mmol). The mixture washeated to 80° C. for 2 hrs. After this time, it was cooled to r.t. anddiluted with EtOAc. The resultant solution was washed sequentially withwater, sat. aq. NaCl solution, and dried over Na₂SO₄. The organic phaseswere filtered and concentrated to dryness. The residue was purified byBiotage Isolera to afford the desired product. LC-MS calculated forC₁₅H₂₂BrN₂O₂ (M+H)⁺: m/z=341.1; found 341.1.

Step 2. tert-Butylmethyl(3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)cyclobutyl)carbamate

A mixture of tert-butyl(3-(5-bromopyridin-2-yl)cyclobutyl)(methyl)carbamate (1.34 g, 3.93mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.5g, 5.89 mmol),[1,1′-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II) (320 mg,0.393 mmol) and potassium acetate (754 mg, 7.85 mmol) in dioxane (14 mL)was stirred at 80° C. for 2 hrs. After cooling to r.t., the reactionmixture was filtered, the solvent was evaporated in vacuo, and the crudematerial was purified by Biotage Isolera. LCMS calculated forC₂₁H₃₄BN₂O₄ (M+H)⁺: m/z=389.3; Found: 389.3.

Step 3. tert-Butyl(3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclobutyl)(methyl)carbamate

To a solution of5-(2,3-dihydro-1H-inden-4-yl)-3-iodo-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine(Example 53, step 3; 456 mg, 0.89 mmol) in 1,4-dioxane (5 mL) and water(1 mL) was added tert-butylmethyl(3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)cyclobutyl)carbamate(450 mg, 1.16 mmol), cesium carbonate (436 mg, 1.34 mmol), and(2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (70 mg, 0.089mmol). The reaction was degassed with N₂ and stirred at 80° C. for 2hrs. After this time, it was cooled to r.t. and diluted with EtOAc. Theresultant solution was washed sequentially with water, sat. aq. NaClsolution, and dried over Na₂SO₄. The organic phases were filtered andconcentrated to dryness. The residue was purified by Biotage Isolera toafford the desired product. LC-MS calculated for C₃₉H₄₄N₅O₄ (M+H)⁺:m/z=646.3; found 646.3.

Step 4.3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-N-methylcyclobutan-1-amine

To a solution of tert-butyl(3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclobutyl)(methyl)carbamate(461 mg, 0.71 mmol) in dichloromethane (2 mL) was added trifluoroaceticacid (2 mL). The reaction was stirred at r.t. for 1 hr. After this time,it was diluted with dichloromethane. The resultant solution was washedsequentially with water, sat. aq. NaCl solution and dried over Na₂SO₄.The organic phases were filtered and concentrated to dryness. Theresidue was used directly in the next step without purification. LC-MScalculated for C₃₄H₃₆N₅O₂ (M+H)⁺: m/z=546.3; found 546.3.

Step 5.N-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclobutyl)-2-hydroxy-N-methylacetamide

To a solution of3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-N-methylcyclobutan-1-amine(20 mg, 0.037 mmol) in dichloromethane (0.5 mL) was added2-hydroxyacetic acid (6 mg, 0.073 mmol), trimethylamine (9 mg, 0.073mmol) and HATU (21 mg, 0.055 mmol). The reaction was stirred at r.t. for1 hr. After this time, it was diluted with dichloromethane. Theresultant solution was washed sequentially with water, sat. aq. NaClsolution, and dried over Na₂SO₄. The organic phases were filtered andconcentrated to dryness. The residue was dissolved in dichloromethane(0.5 mL) and trifluoromethanesulfonic acid (0.1 mL). The reaction wasstirred at r.t. After 30 min, the reaction mixture was quenched with 4NNaOH aq. solution and diluted with dichloromethane. The resultantmixture was washed sequentially with water, sat. aq. NaCl solution anddried over Na₂SO₄. The organic phases were filtered and concentrated todryness. The residue was diluted with MeOH and was purified by prep-LCMS(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% TFA, at flow rate of 60 mL/min). The product wasisolated as the TFA salt. LC-MS calculated for C₂₈H₃₀N₅O₃ (M+H)⁺:m/z=484.2; found 484.2.

Example 179.1-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-1-yl-3-d)-2-hydroxyethan-1-one

Step 1. tert-Butyl 3-hydroxyazetidine-1-carboxylate-3-d

To a solution of tert-butyl 3-oxoazetidine-1-carboxylate (420 mg, 2.45mmol) in MeOH (5 mL) at 0° C. was added sodium borodeuteride (124 mg,2.94 mmol) portionwise. The mixture was warmed to r.t. and stirred for30 minutes. After this time, the resultant solution was concentrated todryness. The residue was purified by Biotage Isolera to afford thedesired product. LC-MS calculated for C₈H₁₅DNO₃ (M+H)⁺: m/z=175.1; found175.1.

Step 2. tert-Butyl 3-iodoazetidine-1-carboxylate-3-d

To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate-3-d (180mg, 1.03 mmol) in THF (4 mL) was added imidazole (141 mg, 2.07 mmol),triphenylphosphine (677 mg, 2.58 mmol) and iodine (394 mg, 1.55 mmol).The mixture was heated to 50° C. and stirred overnight. After this time,the resultant solution was concentrated to dryness. The residue waspurified by Biotage Isolera to afford the desired product. LC-MScalculated for C₈H₁₄DINO₂ (M+H)⁺: m/z=285.0; found 285.0.

Step 3. tert-Butyl 3-(5-bromopyridin-2-yl)azetidine-1-carboxylate-3-d

To a solution of zinc dust (97 mg, 1.48 mmol) in THF (3 mL) was added1,2-dibromoethane (19 mg, 0.1 mmol) and chlorotrimethylsilane (11 mg,0.1 mmol). The reaction was degassed with N₂ and stirred at 60° C. for15 minutes before tert-butyl 3-iodoazetidine-1-carboxylate-3-d (280 mg,0.99 mmol) in DMA (3 mL) was added. The mixture was heated to 60° C. andstirred for 15 minutes before cooled down to r.t. To the cooled mixturewas added 2,5-dibromopyridine (257 mg, 1.08 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1:1) (40mg, 0.049 mmol) and copper iodide (9 mg, 0.049 mmol). The mixture washeated to 80° C. for 2 hrs. After this time, it was cooled to r.t. anddiluted with EtOAc. The resultant solution was washed sequentially withwater, sat. aq. NaCl solution, and dried over Na₂SO₄. The organic phaseswere filtered and concentrated to dryness. The residue was purified byBiotage Isolera to afford the desired product. LC-MS calculated forC₁₃H₁₇DBrN₂O₂ (M+H)⁺: m/z=314.1; found 314.1.

Step 4. tert-Butyl3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)azetidine-1-carboxylate-3-d

A mixture of tert-butyl3-(5-bromopyridin-2-yl)azetidine-1-carboxylate-3-d (206 mg, 0.66 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (250 mg,0.98 mmol),[1,1′-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II) (54 mg,0.066 mmol) and potassium acetate (126 mg, 1.31 mmol) in dioxane (3 mL)was stirred at 80° C. for 2 hrs. After cooling to r.t., the reactionmixture was filtered, the solvent was evaporated in vacuo and the crudematerial was purified by Biotage Isolera. LCMS calculated forC₁₉H₂₉DBN₂O₄ (M+H)⁺: m/z=362.2; Found: 362.2.

Step 5.5-(2,3-Dihydro-1H-inden-4-yl)-3-iodo-6-methoxy-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-pyrazolo[4,3-b]pyridine

To a solution of5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine(Example 53, step 2; 2.5 g, 6.39 mmol) in DMF (5 mL) was addedN-iodosuccinimide (2.87 g, 12.78 mmol). The resulting mixture wasstirred at 60° C. for 1 h. The mixture was cooled to r.t., and2-(trimethylsilyl)ethoxymethyl chloride (1.39 g, 8.31 mmol) and Cs₂CO₃(3.12 g, 9.59 mmol) were added. The reaction mixture was stirred at 80°C. for 1 h. After this time, it was cooled to r.t., diluted with waterand extracted with EtOAc three times. The combined organic phases werewashed with sat. NaCl, dried with Na₂SO₄, filtered and concentrated todryness. The residue was purified by Biotage Isolera to afford thedesired product. LC-MS calculated for C₂₂H₂₉IN₃O₂Si (M+H)+: m/z=522.1;found 522.1.

Step 6. tert-Butyl3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidine-1-carboxylate-3-d

To a solution of5-(2,3-dihydro-1H-inden-4-yl)-3-iodo-6-methoxy-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-pyrazolo[4,3-b]pyridine(70 mg, 0.13 mmol) in 1,4-dioxane (1 mL) and water (0.2 mL) was addedtert-butyl3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)azetidine-1-carboxylate-3-d(63 mg, 0.17 mmol), cesium carbonate (66 mg, 0.20 mmol) and(2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (10 mg, 0.013mmol). The reaction was degassed with N₂ and stirred at 80° C. for 1 hr.After this time, it was cooled to r.t. and diluted with EtOAc. Theresultant solution was washed sequentially with water, sat. aq. NaClsolution, and dried over Na₂SO₄. The organic phases were filtered andconcentrated to dryness. The residue was purified by Biotage Isolera toafford the desired product. LC-MS calculated for C₃₅H₄₅DN₅O₄Si (M+H)⁺:m/z=629.3; found 629.3.

Step 7.3-(6-(Azetidin-3-yl-3-d)pyridin-3-yl)-5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine

To a solution of tert-butyl3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidine-1-carboxylate-3-d(84 mg, 0.134 mmol) in dichloromethane (1 mL) was added trifluoroaceticacid (1 mL). The reaction was stirred at r.t. for 1 hr. After this time,it was diluted with dichloromethane. The resultant solution was washedsequentially with water, sat. aq. NaCl solution and dried over Na₂SO₄.The organic phases were filtered and concentrated to dryness. Theresidue was used directly in the next step without purification. LC-MScalculated for C₂₄H₂₃DN₅O (M+H)⁺: m/z=399.2; found 399.2.

Step 8.1-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-1-yl-3-d)-2-hydroxyethan-1-one

To a solution of3-(6-(azetidin-3-yl-3-d)pyridin-3-yl)-5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine(20 mg, 0.05 mmol) in dichloromethane (0.5 mL) was added 2-hydroxyaceticacid (4 mg, 0.05 mmol), trimethylamine (14 mg, 0.106 mmol) and BOP (21mg, 0.048 mmol). The reaction was stirred at r.t. for 1 hr. After thistime, it was diluted with MeOH and was purified by prep-LCMS (XBridgeC18 column, eluting with a gradient of acetonitrile/water containing0.1% TFA, at flow rate of 60 mL/min). The product was isolated as theTFA salt. LC-MS calculated for C₂₆H₂₅DN₅O₃ (M+H)⁺: m/z=457.2; found457.2.

Example 180. Methyl4-(5-(5-(1-Cyano-2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidine-1-carboxylate

Step 1. tert-Butyl5-chloro-3′,6′-dihydro-[2,4′-bipyridine]-1′(2′H)-carboxylate

A mixture of 2-bromo-5-chloropyridine (2 g, 10.39 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate(3.21 g, 10.39 mmol),[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (0.85 g,1.04 mmol), and K₃PO₄ (4.41 g, 20.79 mmol) in dioxane (20 ml) and water(4.00 ml) was sparged with N₂ and heated to 80° C. for 2 h. The reactionmixture was diluted with EtOAc/MeOH, filtered through celite, and theresidue was purified by ISCO NextGen. LC-MS calculated for C₁₁H₁₂ClN₂O₂(M-C4H₉+H)⁺: m/z=239.1; found 239.0.

Step 2. tert-Butyl 4-(5-chloropyridin-2-yl)piperidine-1-carboxylate

5% Rh/C (0.5 g, 4.86 mmol) was added to a solution of tert-butyl5-chloro-3′,6′-dihydro-[2,4′-bipyridine]-1′(2′H)-carboxylate (1.5 g,5.09 mmol) in EtOH (10 mL) and EtOAc (10 mL). The reaction was purgedwith H₂ and stirred at r.t. connected to a balloon filled with hydrogenfor 16 hrs. After completion, the reaction was filtrated through Celiteusing EtOAc. The filtrate was then concentrated to dryness and used inthe next reaction without further purification. LC-MS calculated forC₁₁H₁₄ClN₂O₂ (M-C4H₉+H)⁺: m/z=241.1; found 241.2.

Step 3. tert-Butyl4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperidine-1-carboxylate

A mixture of tert-butyl 4-(5-chloropyridin-2-yl)piperidine-1-carboxylate(0.75 g, 2.53 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.96 g,3.79 mmol), potassium acetate (0.74 g, 7.58 mmol), XPhos (0.18 g, 0.379mmol) and palladium(II) acetate (0.085 g, 0.379 mmol) in 1,4-dioxane (8mL) was sparged with N₂ and heated to 80° C. for 1 h. After cooling tor.t., the reaction mixture was filtered using EtOAc/MeOH and the solventwas evaporated in vacuo. The crude material was used in the nextreaction without further purification. LC-MS calculated forcorresponding boronic acid C₁₅H₂₄BN₂O₄ (M-C6H₁₀+H)⁺: m/z=307.2; found307.2.

Step 4.4-(3-Iodo-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile

This compound was prepared according to the procedures described inExample 53, step 3, using4-(6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile(Example 75, step 6) instead of5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine asstarting material. LC-MS calculated for C₂₅H₂₂IN₄O₂ (M+H)⁺: m/z=537.1;found 537.1.

Step 5. tert-Butyl4-(5-(5-(1-cyano-2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidine-1-carboxylate

A mixture of4-(3-iodo-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile(1.2 g, 2.237 mmol), tert-butyl4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperidine-1-carboxylate(0.96 g, 2.46 mmol),[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (0.183 g,0.224 mmol) and K₃PO₄ (1.43 g, 6.71 mmol) in 1,4-dioxane (10 mL) andwater (2 mL) was sparged with N₂ and heated to 80° C. for 2 h. Thereaction mixture was diluted with EtOAc/MeOH, filtered through celiteand the residue was purified by ISCO NextGen. LC-MS calculated forC₄₀H₄₃N₆O₄ (M+H)⁺: m/z=671.3; found 671.3.

Step 6.4-(6-Methoxy-1-(4-methoxybenzyl)-3-(6-(piperidin-4-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-M-indene-1-carbonitrile

To tert-butyl4-(5-(5-(1-cyano-2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidine-1-carboxylate(69 mg, 0.103 mmol) was added DCM (0.5 mL) and TFA (1 mL) and themixture was stirred at r.t. for 30 min. The excess TFA was evaporated invacuo, the residue was diluted with DCM and then neutralized usingsaturated NaHCO₃ solution. The organic phase was dried over sodiumsulfate, filtered, and the solvent was evaporated in vacuo. The crudematerial was used in the next reaction without further purification.LC-MS calculated for C₃₅H₃₅N₆O₂ (M+H)⁺: m/z=571.3; found 571.3.

Step 7. Methyl4-(5-(5-(1-cyano-2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidine-1-carboxylate

To a solution of4-(6-methoxy-1-(4-methoxybenzyl)-3-(6-(piperidin-4-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile(12 mg, 0.021 mmol) and trienthylamine (18 μl, 0.126 mmol) in dioxane (1ml) was added methyl carbonochloridate (8 μl, 0.105 mmol). The mixturewas stirred at r.t for 1 h. The reaction was quenched with water,extracted with DCM. The organic phase was dried over Na₂SO₄, filteredand concentrated. The residue was dissolved in DCM (1 mL) and addedtriflic acid (0.1 mL). The mixture was stirred at r.t. for 30 min thenquenched with MeOH and excess DCM was evaporated in vacuo. The residuewas diluted with CH₃CN and filtered through SiliPrep Thiol cartridge andpurified by prep-LCMS (Waters SunFire C18 column, 5 um particle size,30×100 mm) eluting with a gradient of acetonitrile/water containing 0.1%TFA, at flow rate of 60 mL/min). The product was isolated as the TFAsalt. LCMS calculated for C₂₉H₂₉N₆O₃ (M+H)+: m/z=509.2; found 509.2.

Example 181.4-(6-Methoxy-3-(6-(1-(morpholine-4-carbonyl)piperidin-4-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile,Peak 2

Step 1. tert-Butyl4-(5-(5-(1-cyano-2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidine-1-carboxylate(Peak 1 and Peak 2)

The racemic mixture was prepared according to the procedures describedin Example 180, step 5. LC-MS calculated for C₄₀H₄₃N₆O₄ (M+H)⁺:m/z=671.3; found 671.3. Then, two enantiomers were separated with prepFSC (ChrialPAK IH, 21×250 mm, eluting with 30% MeOH in CO₂, at flow rateof 65 mL/min, t_(R, peak 1)=3.7 min, t_(R, peak 2)=4.1 min). Peak 2 wascollected and the solvents were evaporated in vacuo and the residue wasused directly in the next step without further purification.

Step 2.4-(6-Methoxy-1-(4-methoxybenzyl)-3-(6-(piperidin-4-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile(Peak 2)

This compound was prepared according to the procedure described inExample 180, step 6, using tert-butyl4-(5-(5-(1-cyano-2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidine-1-carboxylatePeak 2 as starting material instead of the racemic material (Example180, step 5). LC-MS calculated for C₃₅H₃₅N₆O₂ (M+H)⁺: m/z=571.3; found571.3.

Step 3.4-(6-Methoxy-3-(6-(1-(morpholine-4-carbonyl)piperidin-4-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile(Peak 2)

This compound was prepared according to the procedure described inExample 180, step 7 using4-(6-methoxy-1-(4-methoxybenzyl)-3-(6-(piperidin-4-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrilePeak 2 and morpholine-4-carbonyl chloride as the starting materials. Theproduct was isolated as the TFA salt. LC-MS calculated forC₃₂H₃₄N₇O₃(M+H)⁺: m/z=564.3; found 564.2.

Example 182.4-(3-(6-(1-Acetylpiperidin-4-yl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile,Peak 2

This compound was prepared according to the procedure described inExample 180 and 181, step 7, using4-(6-methoxy-1-(4-methoxybenzyl)-3-(6-(piperidin-4-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile(Example 181, step 2, Peak 2) and acetyl chloride as the startingmaterials. The product was isolated as the TFA salt. LC-MS calculatedfor C₂₉H₂₉N₆O₂(M+H)⁺: m/z=493.2; found 493.2.

Example 183:4-(3-(6-(1-Acetylpyrrolidin-3-yl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile

Step 1. tert-Butyl3-(5-chloropyridin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate

This compound was prepared according to the procedure described inExample 180, step 1, using tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylateinstead of tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(21H)-carboxylateas the starting material. LC-MS calculated for C₁₀H₁₀ClN₂O₂ (M-C₄H₉+H)⁺:m/z=225.0; found 225.0.

Step 2. tert-Butyl 3-(5-chloropyridin-2-yl)pyrrolidine-1-carboxylate,Peak 1 and Peak 2

5% Rh/C (0.58 g, 5.64 mmol) was added to a solution of tert-butyl3-(5-chloropyridin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (1.9 g,6.77 mmol) in THF (10 mL), EtOH (10 mL) and EtOAc (20.00 mL). Thereaction was purged with H₂ and stirred at r.t. connected to a balloonfilled with hydrogen for 20 hrs. After completion, the reaction wasfiltrated through Celite using EtOAc. The filtrate was then concentratedto dryness to afford the racemic mixture. LC-MS calculated forC₁₀H₁₂ClN₂O₂ (M-C4H₉+H)⁺: m/z=227.1; found 227.1. The two enantiomerswere separated with prep FSC (Phenomenex Lux Sum Amylose-1, 21.2×250 mm,eluting with 20% MeOH in CO₂, at flow rate of 70 mL/min,t_(R, peak 1)=2.9 min, t_(R, peak 2)=3.4 min). Peak 2 was collected andthe solvents were evaporated in vacuo and the residue was used directlyto the next step without further purification.

Step 3. tert-Butyl3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrrolidine-1-carboxylate,Peak 2

This compound was prepared according to the procedure described inExample 180, step 3, using tert-butyl3-(5-chloropyridin-2-yl)pyrrolidine-1-carboxylate Peak 2 instead oftert-butyl 4-(5-chloropyridin-2-yl)piperidine-1-carboxylate as thestarting material. LC-MS calculated for corresponding boronic acidC₁₄H₂₂BN₂O₄ (M-C₆H₁₀+H)⁺: m/z=293.2; found 293.1.

Step 4. tert-Butyl3-(5-(5-(1-cyano-2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)pyrrolidine-1-carboxylatePeak A and Peak B

The diastereomeric mixture was prepared according to the proceduresdescribed in Example 180, step 5 using tert-butyl3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrrolidine-1-carboxylate(Peak 2) instead of tert-butyl4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperidine-1-carboxylateas the starting material. LC-MS calculated for C₃₉H₄₁N₆O₄ (M+H)⁺:m/z=657.3; found 657.2. Then, the two diastereomers were separated withprep FSC (Phenomenex Cellulose-1 Sum 21.2×250 mm, eluting with 45% MeOHin CO₂, at flow rate of 100 mL/min, t_(R, peak A)=5.7 min,t_(R, peak B)=6.1 min). Peak A was collected and the solvents wereevaporated in vacuo. The residue was used directly to the next stepwithout further purification.

Step 5.4-(6-Methoxy-1-(4-methoxybenzyl)-3-(6-(pyrrolidin-3-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-JH-indene-1-carbonitrile,Peak A

This compound was prepared according to procedure described in Example180, step 6, using tert-butyl3-(5-(5-(1-cyano-2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)pyrrolidine-1-carboxylate,Peak A as starting material instead of tert-butyl4-(5-(5-(1-cyano-2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidine-1-carboxylate.LC-MS calculated for C₃₄H₃₃N₆O₂ (M+H)⁺: m/z=557.3; found 557.2.

Step 6.4-(3-(6-(1-Acetylpyrrolidin-3-yl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile,Peak A

This compound was prepared according to the procedure described inExample 180, step 7, using4-(6-methoxy-1-(4-methoxybenzyl)-3-(6-(pyrrolidin-3-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile,Peak A and acetyl chloride as the starting materials. The product wasisolated as the TFA salt. LC-MS calculated for C₂₈H₂₇N₆O₂ (M+H)⁺:m/z=479.2; found 479.2.

Example 184.4-(6-Methoxy-3-(6-(1-(morpholine-4-carbonyl)pyrrolidin-3-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile

This compound was prepared according to the procedure described inExample 180, step 7, using4-(6-methoxy-1-(4-methoxybenzyl)-3-(6-(piperidin-4-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile,Peak A and morpholine-4-carbonyl chloride as the starting material. Theproduct was isolated as the TFA salt. LC-MS calculated for C₃₁H₃₂N₇O₃(M+H)⁺: m/z=550.3; found 550.2.

Example 185.4-(3-(1-(Cyanomethyl)-1H-pyrazol-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile

Step 1. tert-Butyl5-(1-cyano-2,3-dihydro-1H-inden-4-yl)-3-(1-(cyanomethyl)-1H-pyrazol-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate

To a solution of tert-butyl5-(1-cyano-2,3-dihydro-1H-inden-4-yl)-3-iodo-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate(Example 75, step 7; 150 mg, 0.291 mmol) in 1,4-dioxane (1.2 mL) andwater (0.24 mL) was added2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetonitrile(81 mg, 0.35 mmol), potassium phosphate (123 mg, 0.581 mmol), andXphosPd G2 (23 mg, 0.029 mmol). The reaction was degassed with N₂ andstirred at 60° C. for 1 hr. After this time, it was cooled to roomtemperature and filtered through a pad of Celite, rinsing with ethylacetate. The residue was purified by silica gel chromatography to affordthe desired product. Separation of enantiomers was achieved by chiralprep-SFC (ChiralPak IB-N Sum 20×250 mm, eluting with 20% MeOH, at 40°C., at a flow rate of 70 mL/min, t_(R, peak 1)=7.1 min,t_(R, peak 2)=7.7 min). Peak 1 was collected and the solvents wereevaporated in vacuo. LCMS calculated for C₂₇H₂₆N₇O₃ (M+H)⁺: m/z=496.2,found: 496.2.

Step 2.4-(3-(1-(Cyanomethyl)-1H-pyrazol-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile

To a solution of tert-butyl5-(1-cyano-2,3-dihydro-1H-inden-4-yl)-3-(1-(cyanomethyl)-1H-pyrazol-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate(36 mg, 0.073 mmol) in dichloromethane (50 μL) was added TFA (50 μL, 6.5mmol) at room temperature. The reaction mixture was stirred for 30 min,then concentrated in vacuo. The residue was diluted with MeOH andpurified by prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). Theproduct was isolated as the TFA salt. LC-MS calculated for C₂₂H₁₈N₇O(M+H)⁺: m/z=396.2, found 396.2.

Example 186.4-(6-Methoxy-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile

tert-Butyl5-(1-cyano-2,3-dihydro-1H-inden-4-yl)-3-iodo-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate(Peak 1, 50 mg, 0.097 mmol) (single enantiomer was obtained by chiralseparation on chiral prep-HPLC Phenomenex Lux Sum Amylose-1, 21.2×250mm, eluting with 15% EtOH in hexanes, at flow rate of 20 mL/min,t_(R, peak 1)=17.5 min, t_(R, peak 2)=23.3 min, 50 mg, 0.097 mmol),(6-(4-methylpiperazin-1-yl)pyridin-3-yl)boronic acid (25.1 mg, 0.116mmol), Xphos-PdG2 (7.6 mg, 9.68 μmol), and NaHCO₃ (16 mg, 0.194 mmol)were placed in a vial and the vial was evacuated and backfilled with N₂three times. After 1,4-dioxane (1 ml) and water (100 μl) were added, thereaction mixture was stirred at 70° C. for 1 h. Then the reaction wasfiltered, and the solvents were evaporated in vacuo. DCM (1 ml) and TFA(0.5 ml) were added and the reaction mixture was stirred at r.t. for 30min. The mixture was then diluted with CH₃CN and water and purified withprep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). Theproduct was isolated as the TFA salt. LC-MS calculated for C₂₇H₂₈N₇O(M+H)⁺: m/z=466.2; found 466.2.

Example 187.3-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-1-yl)propanenitrile

To a solution of3-(6-(azetidin-3-yl)pyridin-3-yl)-5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine(20 mg, 0.039 mmol, Example 172) in MeCN (1 mL) was added3-bromopropanenitrile (15 mg, 0.12 mmol) and cesium carbonate (63 mg,0.19 mmol). The reaction was heated at 50° C. for 2 hr. After this time,it was diluted with dichloromethane. The resultant solution was washedsequentially with water, sat. aq. NaCl solution, and dried over Na₂SO₄.The organic phases were filtered and concentrated to dryness. Theresidue was dissolved in dichloromethane (0.5 mL) andtrifluoromethanesulfonic acid (0.1 mL). The reaction was stirred at r.t.After 30 min, the reaction mixture was quenched with 4N NaOH aq.solution and diluted with dichloromethane. The resultant mixture waswashed sequentially with water, sat. aq. NaCl solution and dried overNa₂SO₄. The organic phases were filtered and concentrated to dryness.The residue was acidified with TFA and MeOH and was purified byprep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). Theproduct was isolated as the TFA salt. LC-MS calculated for C₂₇H₂₇N₆O(M+H)⁺: m/z=451.2; found 451.2.

Example 188.N-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclobutyl)-2-methoxy-N-methylacetamide

This compound was prepared according to the procedures described inExample 178, using 2-methoxyacetic acid instead of 2-hydroxyacetic acidas starting material. The product was isolated as the TFA salt. LCMScalculated for C₂₉H₃₂N₅O₃ (M+H)⁺: m/z=498.2; Found: 498.2.

Example 189.N-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclobutyl)-3-hydroxy-N-methylpropanamide

This compound was prepared according to the procedures described inExample 178, using 3-hydroxypropanoic acid instead of 2-hydroxyaceticacid as starting material. The product was isolated as the TFA salt.LCMS calculated for C₂₉H₃₂N₅O₃ (M+H)⁺: m/z=498.2; Found: 498.2.

Example 190.(S)—N-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclobutyl)-2-hydroxy-N-methylpropanamide

This compound was prepared according to the procedures described inExample 178, using (S)-2-hydroxypropanoic acid instead of2-hydroxyacetic acid as starting material. The product was isolated asthe TFA salt. LCMS calculated for C₂₉H₃₂N₅O₃ (M+H)⁺: m/z=498.2; Found:498.2.

Example 191A.1-(1-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-hydroxyethan-1-one

Step 1. tert-Butyl5-(2,3-dihydro-1H-inden-4-yl)-3-iodo-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate

NIS (0.220 g, 0.978 mmol) was added to a solution of5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine (0.20g, 0.754 mmol) in DMF (10 ml). After stirring at 80° C. for 2 h, thereaction mixture was cooled to r.t., and triethylamine (0.3 ml, 2.2mmol) and Boc-anhydride (0.411 g, 1.89 mmol) were added. Afteradditional stirring at r.t. for 1 h, water was added and theprecipitated product was collected by filtration and air dried. Crudematerial was purified by Biotage Isolera to give a white solid (0.29 g,78%). LCMS calculated for C₂₁H₂₃IN₃O₃ (M+H)⁺: m/z=492.1; found 492.1.

Step 2. tert-Butyl1-(5-bromopyridin-2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

A mixture of 2,5-dibromopyridine (0.49 g, 2.075 mmol), tert-butyl1-(trifluoro-14-boraneyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate,potassium salt (0.30 g, 1.04 mmol), cesium carbonate (1.01 g, 3.11mmol), and cataCXium® A Pd G3 (0.076 g, 0.104 mmol) in toluene (20 ml)and water (2 ml) was heated to 80° C. for 40 hrs. After this time, thesolution was diluted with water and product was extracted with EtOAc.The combined organic layers were washed with sat. aq. NaCl and driedwith Na₂SO₄, then filtered and concentrated to dryness. The residue wasthen purified by silica gel chromatography to afford the desiredproduct. LCMS calculated for C₁₁H₁₂BrN₂O₂ (M-C4H₇)⁺: m/z=283.0; Found:283.1.

Step 3. tert-Butyl1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

A mixture of tert-butyl1-(5-bromopyridin-2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (85 mg,0.25 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(89 mg, 0.35 mmol), PdCl₂dppf. DCM (31 mg, 0.038 mmol), and potassiumacetate (74 mg, 0.75 mmol) in dioxane (2.5 ml) was heated at 85° C. for20 hrs. The reaction mixture was then cooled to r.t. and filteredthrough celite, washed with EtOAc, and concentrated. The residue wasthen purified by silica gel chromatography to afford the desiredproduct. LCMS calculated for C₁₅H₂₂BN₂O₄ (M-C₆H₉)⁺: m/z=305.2; Found:305.1.

Step 4.3-(6-(3-Azabicyclo[3.1.0]hexan-1-yl)pyridin-3-yl)-5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine

A mixture of tert-butyl5-(2,3-dihydro-1H-inden-4-yl)-3-iodo-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate(450 mg, 0.916 mmol), tert-butyl1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(531 mg, 1.374 mmol), SPhos Pd G3 (107 mg, 0.137 mmol), and cesiumcarbonate (895 mg, 2.75 mmol) in dioxane (5 ml) and water (0.5 ml) washeated to 80° C. for 20 hrs. After this time, the solution was cooled tor.t., diluted with water, and the product was extracted with EtOAc. Thecombined organic layers were washed with sat. aq. NaCl and dried overNa₂SO₄, then filtered and concentrated to dryness. The residue was thendissolved in DCM (3 mL), and TFA (2 mL) was added. The solution wasstirred at r.t. for 1 h. The solvent was then removed in vacuo, and theresidue was purified by silica gel chromatography to afford the desiredproduct. LCMS calculated for C₂₆H₂₆N₅O (M+H)⁺: m/z=424.2; Found: 424.4.

Step 5.1-(1-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-hydroxyethan-1-one

A mixture of3-(6-(3-azabicyclo[3.1.0]hexan-1-yl)pyridin-3-yl)-5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine(20 mg, 0.047 mmol), 2-hydroxyacetic acid (4 mg, 0.052 mmol), HATU (20mg, 0.052 mmol), and N,N-diisopropylethylamine (25 μl, 0.142 mmol) inDMF (0.5 ml) was stirred at r.t. for 2 hrs. The mixture was then dilutedwith MeCN and purified by prep-LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min). LCMS calculated for C₂₈H₂₈N₅O₃ (M+H)⁺: m/z=482.2; found 482.4.

Example 191B and Example 191C.1-(1-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-hydroxyethan-1-one,two enantiomers

The two enantiomers of1-(1-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-hydroxyethan-1-onewere separated with chiral SFC (Phenomenex Cellulose-3, 2×250 mm,eluting with 40% MeOH in CO₂, at flow rate of 65 mL/min). Example 191B:peak 1, t_(R)=3.4 min. Example 191C: peak 2, t_(R)=4.1 min. LCMScalculated for C₂₈H₂₈N₅O₃ (M+H)⁺: m/z=482.2; found 482.4.

Example 192.(1-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)((R)-4-methylmorpholin-3-yl)methanone

This compound was prepared according to the procedure described inExample 191, using (R)-4-methylmorpholine-3-carboxylic acidhydrochloride instead of 2-hydroxyacetic acid. LC-MS calculated forC₃₂H₃₅N₆O₃ (M+H)⁺: m/z=551.3; found 551.3.

Example 193.5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-3-(6-(3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine

A mixture of3-(6-(3-azabicyclo[3.1.0]hexan-1-yl)pyridin-3-yl)-5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine(20 mg, 0.047 mmol), tetrahydro-4H-pyran-4-one (14 mg, 0.142 mmol), andsodium triacetoxyhydroborate (20 mg, 0.094 mmol) in DCM (1 ml) wasstirred at r.t. for 20 hrs. After this time, the solution was quenchedwith TFA (0.5 mL). The mixture was diluted with MeCN and purified byprep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₃₁H₃₄N₅O₂ (M+H)⁺: m/z=508.3; found 508.4.

Example 194A.2-(1-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)ethan-1-ol

A mixture of3-(6-(3-azabicyclo[3.1.0]hexan-1-yl)pyridin-3-yl)-5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine(30 mg, 0.071 mmol), 2-((tert-butyldimethylsilyl)oxy)acetaldehyde (37mg, 0.213 mmol), and sodium triacetoxyhydroborate (30 mg, 0.142 mmol) inDCM (1 ml) was stirred at r.t. for 20 hrs. After this time, the solutionwas diluted with water, and the product was extracted with DCM. Thecombined organic layers were washed with sat. aq. NaCl and dried withNa₂SO₄, then filtered and concentrated to dryness. The residue was thendissolved in DCM (1 mL) and TFA (1 mL) was added. The mixture wasstirred at r.t. for 1 h and purified by prep-LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min). LCMS calculated for C₂₈H₃₀N₅O₂ (M+H)⁺:m/z=468.2; found 468.4.

Example 194B and Example 194C.2-(1-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)ethan-1-ol,two enantiomers

The two enantiomers of2-(1-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)ethan-1-olwere separated with chiral prep-HPLC (Phenomenex Lux Sum Cellulose-2,21.2×250 mm, eluting with 30% EtOH in hexanes, at flow rate of 20mL/min). Example 194B: peak 1, t_(R)=14.4 min. Example 194C: peak 2,t_(R)=16.1 min. LCMS calculated for C₂₈H₃₀N₅O₂ (M+H)⁺: m/z=468.2; found468.4.

Example 195.3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-1-((R)-4-methylmorpholine-3-carbonyl)pyrrolidine-3-carbonitrile

Step 1. tert-Butyl3-(5-bromopyridin-2-yl)-3-cyanopyrrolidine-1-carboxylate

To a solution of tert-butyl 3-cyanopyrrolidine-1-carboxylate (1.18 g,6.01 mmol) and 5-bromo-2-fluoropyridine (1.06 g, 6.01 mmol) in THF (30ml) at 0° C. was added sodium bis(trimethylsilyl)amide (6.6 ml, 6.6mmol) dropwise. The resulting solution was stirred at 0° C. for 1 hr,then warm to r.t. and stirred for additional 2 hrs. After this time, thesolution was quenched with water, and the product was extracted withDCM. The combined organic layers were washed with sat. aq. NaCl anddried with Na₂SO₄, then filtered and concentrated to dryness. Theresidue was then purified by silica gel chromatography to afford thedesired product. LCMS calculated for C₁₁H₁₁BrN₃O₂ (M-C4H₇)⁺: m/z=296.0;Found: 296.0.

Step 2. tert-Butyl3-cyano-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrrolidine-1-carboxylate

A mixture of tert-butyl3-(5-bromopyridin-2-yl)-3-cyanopyrrolidine-1-carboxylate (1.72 g, 4.88mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.74g, 6.84 mmol), PdCl₂dppf. DCM (0.6 g, 0.732 mmol), and potassium acetate(1.44 g, 14.65 mmol) in dioxane (30 ml) was heated at 85° C. for 20 hrs.The reaction mixture was then filtered through celite, washed withEtOAc, and concentrated. The residue was then purified by silica gelchromatography to afford the desired product. LCMS calculated forC₁₇H₂₃BN₃O₄ (M-C4H₇)⁺: m/z=344.2; Found: 344.1.

Step 3.3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)pyrrolidine-3-carbonitrile

A mixture of tert-butyl5-(2,3-dihydro-1H-inden-4-yl)-3-iodo-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate(500 mg, 1.02 mmol), tert-butyl3-cyano-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrrolidine-1-carboxylate(813 mg, 2.04 mmol), SPhos Pd G3 (159 mg, 0.204 mmol), and cesiumcarbonate (995 mg, 3.05 mmol) in dioxane (6 ml) and water (0.6 ml) washeated to 80° C. for 2 hrs. After this time, the solution was cooled tor.t., diluted with water, and the product was extracted with EtOAc. Thecombined organic layers were washed with sat. aq. NaCl and dried withNa₂SO₄, then filtered and concentrated to dryness. The residue was thendissolved in DCM (3 mL) and TFA (2 mL) was added. The solution wasstirred at r.t. for 1 h. The solvent was then removed in vacuo, and theresidue was purified by silica gel chromatography to afford the desiredproduct. LCMS calculated for C₂₆H₂₅N₆O (M+H)⁺: m/z=437.2; Found: 437.4.

Step 4.3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-1-((R)-4-methylmorpholine-3-carbonyl)pyrrolidine-3-carbonitrile

A mixture of3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)pyrrolidine-3-carbonitrile(20 mg, 0.046 mmol), (R)-4-methylmorpholine-3-carboxylic acidhydrochloride (9 mg, 0.050 mmol), HATU (19 mg, 0.050 mmol), andN,N-diisopropylethylamine (24 μl, 0.137 mmol) in DMF (0.5 ml) wasstirred at r.t. for 20 hrs. The mixture was then diluted with MeCN andpurified by prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₃₂H₃₄N₇O₃ (M+H)⁺: m/z=564.3; found 564.3.

Example 196.(R)-4-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-1-(4-methylmorpholine-3-carbonyl)piperidine-4-carbonitrile

This compound was prepared according to the procedure described inExample 165, using (R)-4-methylmorpholine-3-carboxylic acidhydrochloride instead of 2-hydroxyacetic acid. LC-MS calculated forC₃₃H₃₆N₇O₃ (M+H)⁺: m/z=578.3; found 578.3.

Example 197.1-(1-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-hydroxyethan-1-one

Step 1. tert-Butyl1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

A mixture of tert-butyl1-(4-chloro-1H-pyrazol-1-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(150 mg, 0.529 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (188 mg,0.740 mmol), Pd₂dba₃ (48 mg, 0.053 mmol), XPhos (50 mg, 0.106 mmol), andpotassium acetate (156 mg, 1.586 mmol) in dioxane (5.3 ml) was heated at100° C. for 20 hrs.

The reaction mixture was then filtered through celite, washed withEtOAc, and concentrated. The residue was then purified by silica gelchromatography to afford the desired product. LCMS calculated forC₁₅H₂₃BN₃O₄ (M-C4H₇)⁺: m/z=320.2; Found: 320.1.

Step 2.3-(1-(3-Azabicyclo[3.1.0]hexan-1-yl)-1H-pyrazol-4-yl)-5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine

A mixture of tert-butyl5-(2,3-dihydro-1H-inden-4-yl)-3-iodo-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate(150 mg, 0.305 mmol), tert-butyl1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(172 mg, 0.458 mmol), SPhos Pd G3 (48 mg, 0.061 mmol), and cesiumcarbonate (298 mg, 0.916 mmol) in dioxane (2 ml) and water (0.200 ml)was heated at 80° C. for 2 hrs. After this time, the solution was cooledto r.t., diluted with water, and the product was extracted with EtOAc.The combined organic layers were washed with sat. aq. NaCl and driedwith Na₂SO₄, then filtered and concentrated to dryness. The residue wasthen dissolved in DCM (3 mL) and

TFA (2 mL) was added. The solution was stirred at r.t. for 1 h. Thesolvent was then removed and the residue was purified by silica gelchromatography to afford the desired product. LCMS calculated forC₂₄H₂₅N₆O (M+H)⁺: m/z=413.2; Found: 413.4.

Step 3.1-(1-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-hydroxyethan-1-one

A mixture of3-(1-(3-azabicyclo[3.1.0]hexan-1-yl)-1H-pyrazol-4-yl)-5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine(10 mg, 0.024 mmol), 2-hydroxyacetic acid (2 mg, 0.024 mmol), HATU (14mg, 0.036 mmol), and N,N-diisopropylethylamine (9 μl, 0.048 mmol) in DMF(0.5 ml) was stirred at r.t. for 1 hr. The mixture was then diluted withMeCN and purified by prep-LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min). LCMS calculated for C₂₆H₂₇N₆O₃ (M+H)⁺: m/z=471.2; found 471.2.

Example 198.3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-1(2-hydroxyacetyl)pyrrolidine-3-carbonitrile

This compound was prepared according to the procedure described inExample 195, using 2-hydroxyacetic acid instead of(R)-4-methylmorpholine-3-carboxylic acid hydrochloride. LC-MS calculatedfor C₂₈H₂₇N₆O₃ (M+H)⁺: m/z=495.2; found 495.1.

Example 199.(S)-4-((5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)methyl)-1,3-dimethylpiperazin-2-one

This compound was prepared according to the procedure described inExample 160, using (S)-1,3-dimethylpiperazin-2-one instead ofpiperidin-4-ol. LC-MS calculated for C₂₈H₃₁N₆O₂ (M+H)⁺: m/z=483.2; found483.2.

Example 200.(1R,4R)-5-((5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)methyl)-2-oxa-5-azabicyclo[2.2.1]heptane

This compound was prepared according to the procedure described inExample 160, using (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane instead ofpiperidin-4-ol. LC-MS calculated for C₂₇H₂₈N₅O₂ (M+H)⁺: m/z=454.2; found454.4.

Example a FGFR Enzymatic Assay

The inhibitor potency of the exemplified compounds was determined in anenzyme discontinuous assay that measures peptide phosphorylation usingFRET measurements to detect product formation. Inhibitors were seriallydiluted in DMSO and a volume of 0.2 μL was transferred to the wells of a384-well plate. A 5 μL/well volume of enzyme isoforms of FGFR (-1, -2,-3 wild-type and mutant isoforms, -4) including phosphorylated andun-phosphorylated proteins diluted in assay buffer (50 mM HEPES, 10 mMMgCl₂, 1 mM EGTA, 0.01% Tween-20, 5 mM DTT, pH 7.5) was added to theplate and pre-incubated with inhibitor for 5 to 15 minutes at ambienttemperature. Appropriate controls (enzyme blank and enzyme with noinhibitor) were included on the plate. The reaction was initiated by theaddition of a 5 μL/well volume containing both biotinylatedEQEDEPEGDYFEWLE peptide substrate (SEQ ID NO. 1) and ATP in assaybuffer. The 10 μL/well reaction concentration of the peptide substratewas 500 nM whereas the ATP concentration was maintained near or belowthe ATP Km. The ATP Km values were pre-determined in a separate seriesof experiments. The reaction plate was incubated at 25° C. for 1 hr andthe reactions were ended with the addition of 5 μL/well of quenchsolution (50 mM Tris, 150 mM NaCl, 0.5 mg/mL BSA, pH 7.8; 45 mM EDTA,600 nM staurosporin, with Perkin Elmer Lance Reagents at 3.75 nMEu-antibody PY20 and 180 nM APC-Streptavidin). The plate was allowed toequilibrate for ˜10 minutes at ambient temperature before scanning on aPheraStar plate reader (BMG Labtech) instrument.

Either GraphPad prism or XLfit was used to analyze the data. The IC₅₀values were derived by fitting the data to a four parameter logisticequation producing a sigmoidal dose-response curve with a variable Hillcoefficient. Prism equation: Y=Bottom+(Top−Bottom)/(1+10{circumflex over(()}(Log IC₅₀−X)*Hill slope)); XLfit equation:Y=(A+((B−A)/(1+((X/C){circumflex over ( )}D)))) where X is the logarithmof inhibitor concentration and Y is the response. Compounds having anIC₅₀ of 1 μM or less are considered active.

GraphPad prism3 was used to analyze the data. The IC₅₀ values werederived by fitting the data to the equation for a sigmoidaldose-response with a variable slope.Y=Bottom+(Top−Bottom)/(1+10{circumflex over (()}(Log IC₅₀−X)*HillSlope))where X is the logarithm of concentration and Y is the response.Compounds having an IC₅₀ of 1 μM or less are considered active.

Table 1 provides IC₅₀ data for compounds of the invention assayed in theFGFR Enzymatic Assay after dilution in assay buffer, added to the plateand pre-incubated for 4 hours. The symbol: “+” indicates an IC₅₀ lessthan 6 nM; “++” indicates an IC₅₀ greater than or equal to 6 nM but lessthan 40 nM; “+++” indicates an IC₅₀ greater than or equal to 40 nM butless than 100 nM; and “++++” indicates an IC₅₀ greater than or equal to100 nM.

The data in Table 1 was measured in wild-type un-phosphorylated FGFR1,FGFR2, FGFR3, and FGFR4 proteins.

TABLE 1 Example No. FGFR3 FGFR1 FGFR4 FGFR2  1 + ++++ ++++ ++  2 + ++++++ +  3 + +++ +  4 + ++++ ++++ ++  5 + ++++ ++++ ++  6 + ++++ +  7 ++++  8 + ++++  9 + +++  10 + +++ ++++ ++  11 + +++ +  12 + +++ +  13 +++++  14 + +++  15 + +++  16 + +++ ++++ +  17 + +++ ++++ +  18 + +++++++ +  19 + +++ ++++ +  20 + +++ ++++ +  21 + +++ +++ +  22 + +++ +++ + 23 + ++++ ++++ +  24 + ++ ++ +  25 + ++ +++ +  26 + ++++  27 + ++++++ +  28 + +++ ++++ +  29 + +++ +++ +  30 + ++++ +++ ++  31 + +++ +++ + 32 + ++++  33 + +++ ++++ +  34 + +++ ++++ +  35 + +++  36 + +++ ++++ ++ 37 + ++++  38 + ++++ ++++ ++  39 + +++ ++  40 + ++++ ++++ ++  41 + ++++++ +  42 + +++ ++++ +  43 + ++++ +  44 + ++++ ++++ ++  45 + ++++ + 46 + ++++ +  47 + +++  48 + +++ +  49 + +++  50 + ++++ +  51 + +++ + 52 + ++++ ++++ ++  53 + +++  54 + +++  55 + ++++  56 + ++++ ++++ ++ 57 + ++++ ++++ +  58 + +++ +++ +  59 + ++ ++ +  60 + ++ ++ +  61 + +++++++ +  62 + ++ ++++ +  63 + ++ +++ +  64 + ++  65 + ++++ +  66 + ++++++++ +  67 + ++++  68 + +++ +  69 + ++++  70 + ++++  71 + ++++  72 + ++++++ +  73 + +++ ++  74 + ++ ++++ +  75 + ++ +  76 + ++ +  77 + ++++++++ +  78 + ++++ ++++ +  79 + +++ +  80 + +++ +  81 + ++ +  82 + ++ + 83 + ++ +  84 + +++ ++++ +  85 + +++ +++ +  86 + ++++ +  87 + +++ +++ + 88 + +++  89 + ++++ +  90 + ++++ ++  91 + ++++ ++  92 + ++++ ++  93 +++++ ++  94 + ++++ ++  95 + +++ ++++ ++  96 + +++ ++++ ++  97 + +++ ++++++  98 + +++ ++++ +  99 + ++ ++ + 100 + ++ ++ + 101 + ++ ++ + 102 + ++++ + 103 + ++ ++ + 104 + ++ ++ + 105 + ++ ++ + 106 + ++ ++ + 107 + ++++ + 108 + ++ ++ + 109 + ++ ++ + 110 + ++ ++ + 111 + + +++ + 112 + ++++++ + 113 + ++ +++ + 114 + ++ ++ + 115 + ++ ++ + 116 + ++ +++ + 117 + +++++ + 118 + ++ +++ + 119 + ++ +++ + 120 + ++ +++ + 121 + ++ +++ + 122 +++ +++ + 123 + ++ ++ + 124 + ++ +++ + 125 + ++ ++ + 126 + ++ ++ + 127 +++ +++ + 128 + ++ +++ + 129 + ++ ++ + 130 + ++ ++ + 131 + ++ ++ + 132 +++ +++ + 133 + ++ +++ + 134 + ++ +++ + 135 + ++ ++ + 136 + ++ ++ + 137 +++ +++ + 138 + ++ +++ + 139 + ++ ++ + 140 + ++ +++ + 141 + ++ ++ + 142 +++ +++ + 143 + ++ ++ + 144 + ++ ++ + 145 + ++ ++ + 146 + ++ ++ + 147 +++ +++ + 148 + ++ +++ + 149 + ++ ++ + 150 + +++ +++ + 151 + ++ +++ +152 + +++ +++ + 153 + ++ +++ + 154 + +++ ++++ + 155 + ++ ++ + 156 + ++++ + 157 + +++ +++ + 158 + ++ +++ + 159 + ++ ++ + 160 + +++ +++ + 161 ++++ +++ + 162 + +++ ++++ + 163 + +++ +++ + 164 + +++ +++ + 165 + ++ ++ +166 + +++ +++ + 167 + +++ +++ + 168 + ++ ++ + 169 + ++ +++ + 170 + ++++ + 171 + ++ ++ + 172 + +++ +++ + 173 + ++ ++ + 174 + ++ +++ + 175 + ++++ + 176 + ++ +++ + 177 + +++ +++ + 178 + ++ ++ + 179 + ++ ++ + 180 ++++ +++ + 181 + ++ ++ + 182 + ++ ++ + 183 + ++ ++ + 184 + ++ ++ + 185 ++++ ++ + 186 + ++ ++ + 187 + ++ ++ + 188 + ++ ++ + 189 + ++ ++ + 190 +++ +++ +   191A + ++ ++ +   191B + ++ +   191C + ++ + 192 + ++ + 193 +++ ++ +   194A + ++ ++ +   194B + ++ +   194C + ++ + 195 + ++ + 196 +++ + 197 + ++ + 198 + ++ +++ + 199 + +++ +++ + 200 + +++ +++ + * Blankentries were not tested.

Compounds disclosed in US 2018/0072718 were also evaluated for FGFR3inhibitory activity according to the protocol described above.Accordingly, Table 2 provides IC₅₀ data for compounds of US2018/0072718. The symbol: “+” indicates an IC₅₀ less than 6 nM; “++”indicates an IC₅₀ greater than or equal to 6 nM but less than 60 nM;“+++” indicates an IC₅₀ greater than or equal to 60 nM but less than 200nM; and “++++” indicates an IC₅₀ greater than or equal to 200 nM.

TABLE 2 Example No. from US2018/0072718 Structure Inhibition of FGFR3 2

+++ 3

+++ 4

++++ 19

++++ 54

++++ 62

++++ 64

++++ 74

++++ 75

++++ 76

++++ 77

++++

Example B: Luminescent Viability Assay

RT112 cells (cell lines and genetic profiles further detailed in Table3) are purchased from ATCC (Manassas, Va.) and maintained in RPMI, 10%FBS (Gibco/Life Technologies). To measure the effect of test compoundson the viability of cells, the cells are plated with RPMI 10% FBS (5×103cells/well/in 50 μL) into black 96-well Greiner polystyrene in thepresence or absence of 50 ul of a concentration range of test compounds.After 3 days, 100 ul of CellTiter-Glo Reagent (Promega) is added.Luminescence is read with a TopCount (PerkinElmer). IC₅₀ determinationis performed by fitting the curve of percent inhibition versus the logof the inhibitor concentration using the GraphPad Prism 5.0 software.

TABLE 3 Cell line Histology FGFR2/3 alteration RT-112/84 BladderFGFR3-TACC3 RT112 Bladder FGFR3-TACC3 RT-112 V555M* Bladder FGFR3-TACC3V555M UM-UC-14 Bladder FGFR3 S249C RT-4 Bladder FGFR3-TACC3 SW-780Bladder FGFR3-BAIAP2L1 KMS-11 Multiple Myeloma IgH-FGFR3 translocation +FGFR3 Y373C OPM-2 Multiple Myeloma IgH-FGFR3 translocation + FGFR3 K650EKATO-III Stomach FGFR2 amplification SNU-16 Stomach FGFR2 amplificationAN3CA Endometrial FGFR2 N310R/N549K Ba/F3-FGFR2-BICC1 Engineered systemFGFR2-BICC1** Ba/F3-TEL-FGFR3 Engineered system TEL-FGFR3Ba/F3-TEL-FGFR3 Engineered system TEL-FGFR3 V555M V555M Ba/F3-TEL-FGFR3Engineered system TEL-FGFR3 V555L V555L *RT112 V555M: V555M mutation wasengineered using CRISPR-mediated genome editing. **FGFR2-BICC1 fusionrepresents the most prevalent FGFR2 alteration in cholangiocarcinoma

Example C: pFGFR2 and pFGFR1,3 Functional Cell HTRF Assay

To measure phosphorylated Fibroblast Growth Factor Receptor 2 (FGFR2),KATOIII cells (Human Gastric Carcinoma) are purchased from ATCC andmaintained in Iscoves with 20% FBS (Gibco/Life Technologies). For thepFGFR2 assay, KATOIII cells are plated overnight in 5% FBS and Iscove'smedium at 5×10⁴ cells/well into Corning 96-well flat-bottom tissueculture treated plates. The next morning, 50 μl of fresh media with 0.5%FBS is incubated in the presence or absence of a concentration range oftest compounds also at 50 ul, for 1 hour at 37° C., 5% CO₂. Cell arewashed with PBS, lysed with Cell Signaling Lysis Buffer with standardProtease inhibitors for 45 min at room temperature. 4 μl total of CisBio Anti Phospho-YAP d2 and Cis Bio Anti Phospho-YAP Cryptate togetherare added to the lysate and mixed well (following directions of thekit). 16 μl is then transferred to 384 well Greiner white plates andstored at 4° C. overnight in the dark. Plates are read on the Pherastarplate reader at 665 nm and 620 nm wavelengths. IC₅₀ determination isperformed by fitting the curve of inhibitor percent inhibition versusthe log of the inhibitor concentration using the GraphPad Prism 5.0software.

To measure phosphorylated Fibroblast Growth Factor Receptor 3 (FGFR3),in house stable cell lines BAF3-TEL-FGFR1 or BAF3-TEL-FGFR3 aremaintained in RPMI with 10% FBS and 1 ug/ml puromycin (Gibco/LifeTechnologies). For the assay, 12 nl of BAF3-TEL-FGFR1 or BAF3-TEL-FGFR3cells in serum free and puromycin free RPMI media at 1×10⁶ cell/ml areadded to 384 Greiner white plate already containing 20 nl dots ofcompounds at a concentration range. The plates are gently shaken (100rpm) for 2 minutes at room temperature to mix well and incubate for 2hours in a single layer at 37° C., 5% CO₂. 4 μl/well of 1/25 dilution oflysis buffer #3 (Cis Bio) is added with standard Protease inhibitors andshaken at 200 rpm at room temperature for 20 minutes. 4 μl total of theCis Bio Tb-pFGFR Ab (10 ng) and d2-FGFR3 (1 ng) together are added tothe lysate and mixed well. The plates are sealed and incubated at roomtemperature overnight in the dark. The plates are read on the Pherastarplate reader at 665 nm and 620 nm wavelengths. IC₅₀ determination isperformed by fitting the curve of inhibitor percent inhibition versusthe log of the inhibitor concentration using the GraphPad Prism 5.0software.

Example D: pFGFR3 Functional Whole Blood HTRF Assay

To measure phosphorylated Fibroblast Growth Factor Receptor 3 (FGFR3) ina whole blood assay, in house stable cell lines BAF3-TEL-FGFR3 aremaintained in RPMI with 10% FBS and 1 pg/ml puromycin (Gibco/LifeTechnologies). For the assay, 100 ul BAF3-TEL-FGFR3 cells in 10% FBS andpuromycin free RPMI media at 5×10⁴ cell/well are added to fibronectincoated 96 well tissue culture plate (5 ug/ml) overnight at 37° C., 5%CO₂. The next day, serum is separated from the top of the blood by a lowspeed spin, 1200, RPM, and heat inactivated by incubating at 56° C. for15 minutes. 30 μl of the cooled serum is added to a 96 well plate predotted with 70 nM dots of compounds at a concentration range. Cellplates are washed gently with media, all the blood/compound mixture isadded to the plates, and the plates are incubated for 2 hours at 37° C.,5% CO₂. Blood from the plate is gently washed twice by adding media tothe side of the wells and then dumping media from the plate, andallowing the plate to briefly sit on a paper towel to drain. 70 μl/wellof 1× of lysis buffer #1 (Cis Bio) are added with standard Proteaseinhibitors, and are shaken at 400 rpm at room temperature for 30minutes. Following lysis, the plate is spun down for 5 minutes and 16 uLof lysate is transferred into a 384-well small volume plate. 4 μl totalof the Cis Bio Tb-pFGFR Ab (10 ng) and d2-FGFR3 (1 ng) together areadded to the lysate and mixed well. The plates are sealed and incubatedat room temperature overnight in the dark. Plates are read on thePherastar plate reader at 665 nm and 620 nm wavelengths. IC₅₀determination is performed by fitting the curve of inhibitor percentinhibition versus the log of the inhibitor concentration using theGraphPad Prism 5.0 software.

Example E: KATOIII Whole Blood pFGFR2α ELISA Assay

To measure tyrosine-phosphorylated Fibroblast Growth Factor Receptor 2alpha (FGFR2a) in KATO III spiked whole blood assay, KATO III cells arepurchased from ATCC and maintained in Iscove's medium with 20% FBS(Gibco/Life Technologies). To measure the inhibition of FGFR2a activityof test compounds, the cells are resuspended with Iscove's, 0.2% FBS at5×10⁶ cells/ml. 50 μL of the cells are then spiked into a 96-deep well 2ml polypropylene assay block (Costar) in the presence or absence of aconcentration range of test compounds and 300 ul human heparinized wholeblood (Biological Specialty Corp, Colmar Pa.). After 4 hours incubationin 37° C., the red cells are lysed using Qiagen EL buffer and the celllysates are resuspended in lysis buffer (Cell Signaling) containingstandard protease inhibitor cocktail (Calbiochem/EMD) and PMSF (Sigma)for 30 minutes ice. The lysates are transferred to a standard V bottompropylene tissue culture plate and frozen overnight at −80° C. Samplesare tested an in an R & D Systems DuoSet IC Human Phospho-FGF R2α ELISAand the plate is measured using a SpectraMax M5 microplate set to 450 nmwith a wavelength correction of 540. IC₅₀ determination is performed byfitting the curve of inhibitor percent inhibition versus the log of theinhibitor concentration using the GraphPad Prism 5.0 software.

Example F: Inhibition of FGFR Pathway

The cellular potency of compounds was determined by measuringphosphorylation of FGFR or FGFR downstream effectors Fibroblast growthfactor receptor substrate 2 (FRS2) and extracellular-signal-regulatedkinase (ERK) in cell lines with FGFR2/3 alterations.

To measure phosphorylated Fibroblast growth factor receptor, Fibroblastgrowth factor receptor substrate 2 (FRS2) andextracellular-signal-regulated kinase (ERK), cells (details regardingthe cell lines and types of data produced are further detailed in Table4) were seeded in 6 well plates overnight in 10% FBS and RPMI medium at5-7.5×10⁵ cells/well into Corning 6-well tissue culture treated plates.The next morning, 2 ml of fresh media with 10% FBS is incubated in thepresence or absence of a concentration range of test compounds for 4hours at 37° C., 5% CO₂. Cells were washed with PBS and lysed with CellSignaling Lysis Buffer with standard Protease inhibitors. 20-40 μg oftotal protein lysates were applied to western blot analysis usingantibodies: phosphor-FRS2 Tyr436 (AF5126) from R&D Systems (Minneapolis,Minn.)), phosphor-FGFR-Tyr653/654 (#2476S), phospho-ERK1/2-Thr202/Tyr204(#9101L) and total-ERK1/2 (#9102L) from Cell Signaling Technologies(Danvers, Mass.)).

TABLE 4 FGFR2/3 Cell line Histology alteration Readout RT-112/84 BladderFGFR3-TACC3 pFRS2, pERK RT112 V555M Bladder FGFR3-TACC3 pFRS2, pERKV555M UM-UC-14 Bladder FGFR3 S249C pFRS2, pERK KMS-11 Multiple IgH-FGFR3pFRS2, pERK Myeloma translocation + FGFR3 Y373C KATO-III Stomach FGFR2pFGFR, pERK amplification SNU-16 Stomach FGFR2 pFGFR, pERK amplification

Example G: Activity on In Vivo Tumor Models Harboring FGFR2/3 Alteration

In vivo activity of compounds was determined by measuring tumor growthwhen treated with various doses of compounds in FGFR2/3 altered models.

RT112/84 tumor cells (85061106, ECACC, UK) were maintained asrecommended by the source (tumor models are further detailed in Table5). On Day 0 of the experiments, 2.0×10⁶ RT112/84 cells were inoculatedwith a 1:1 PBS to Matrigel (354263, Corning) subcutaneously into theright hind flank of female NSG mice (Jackson). Treatment with compoundsat 0 (Vehicle), 100 mg/kg, 30 mg/kg or 10 mg/kg PO QD was initiated onDay 7 after tumor inoculation, when tumors averaged approximately 200mm³, and continued until the end of study. Mice were monitored for tumorgrowth and overt tolerability over the course of the experiment. Tumorvolume was calculated using the formula (L×W²)/2, where L and W refer tothe length and width dimensions, respectively. Tumor growth inhibition(TGI) was calculated using the formula (1−(V_(T)/V_(C)))*100 where V_(T)is the tumor volume of the treatment group on the last day of treatment,and V_(C) is the tumor volume of the control group on the last day oftreatment. One-way ANOVA was used to determine statistical differencesbetween treatment groups at the end of the study.

TABLE 5 Tumor model Histology FGFR2/3 alteration RT-112/84 BladderFGFR3-TACC3 RT112 V555M Bladder FGFR3-TACC3 V555M UM-UC-14 Bladder FGFR3S249C KMS-11 Multiple Myeloma IgH-FGFR3 translocation + FGFR3 Y373CKATO-III Stomach FGFR2 amplification SNU-16 Stomach FGFR2 amplificationBa/F3-TEL- Engineered system TEL-FGFR3 V555M FGFR3 V555M

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including all patent,patent applications, and publications, cited in the present applicationis incorporated herein by reference in its entirety.

What is claimed is:
 1. A compound having Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: Cy¹ is selectedfrom phenyl and 5-6 membered heteroaryl; wherein each 5-6 memberedheteroaryl has at least one ring-forming carbon atom and 1, 2, or 3ring-forming heteroatoms independently selected from N, O, and S;wherein the N and S are optionally oxidized; wherein a ring-formingcarbon atom of 5-6 membered heteroaryl is optionally substituted by oxoto form a carbonyl group; and wherein the phenyl and 5-6 memberedheteroaryl are each optionally substituted with 1, 2, 3 or 4substituents independently selected from R¹⁰; R¹ is selected from halo,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,4-5 membered heterocycloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₃alkoxy-C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkoxy, HO—C₁₋₃ alkoxy, HO—C₁₋₃alkyl, cyano-C₁₋₃ alkyl, H₂N—C₁₋₃ alkyl, C₁₋₆ alkylamino,di(C₁₋₆alkyl)amino, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆alkylcarbonyl, and C₁₋₆ alkoxycarbonyl; wherein optionally one or more Hatoms of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₆ cycloalkyl, 4-5 membered heterocycloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkoxy, HO—C₁₋₃alkoxy, HO—C₁₋₃ alkyl, cyano-C₁₋₃ alkyl, H₂N—C₁₋₃ alkyl, C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆alkylcarbonyl, and C₁₋₆ alkoxycarbonyl are replaced by one or more Datoms; each R² and R³ are independently selected from C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ alkylene,4-10 membered heterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ alkylene, 5-10membered heteroaryl-C₁₋₃ alkylene, halo, CN, NO₂, OR^(a2), SR^(a2),C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2) NR^(c2)C(O)R^(b2) NR^(c2)C(O)OR^(a2),NR^(c2)C(O)NR^(c2)R^(d2), C(═NR^(e2))R^(b2), C(═NOR^(a2))R^(b2),C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)C(═NR^(e2))NR^(c2)R^(a2),NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2),S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃alkylene are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²¹; or two adjacent R² substituents on thephenyl ring, taken together with the atoms to which they are attached,form a fused 5- or 6-membered cycloalkyl ring, or a fused 5- or6-membered heterocycloalkyl ring; wherein each fused 5- or 6-memberedheterocycloalkyl ring has at least one ring-forming carbon atom and 1 or2 ring-forming heteroatoms independently selected from N, O, and S;wherein a ring-forming carbon atom of each fused 5- or 6-memberedheterocycloalkyl ring is optionally substituted by oxo to form acarbonyl group; and wherein the fused 5- or 6-membered cycloalkyl ring,and the fused 5- or 6-membered heterocycloalkyl ring are each optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR²¹; n is selected from 0, 1, 2, and 3; each R¹⁰ is independentlyselected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 4-12 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, C₃₋₁₀ alkylene, 4-12 memberedheterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 memberedheteroaryl-C₁₋₃ alkylene, halo, D, CN, NO₂, OR^(a1) SR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1),NR^(c1)C(O)NR^(c1)R^(d1), C(═NR^(e1))R^(b1), C(═NOR^(a1))R^(b1),C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1),S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-12 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-12 membered heterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 memberedheteroaryl-C₁₋₃alkylene are each optionally substituted with 1, 2, 3, or4 substituents independently selected from R¹¹; each R¹¹ isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ alkylene, 5-10 memberedheteroaryl-C₁₋₃alkylene, halo, D, CN, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3),NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3),and S(O)₂NR^(c3)R^(d3); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R¹²; each R¹² isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, 4-7membered heterocycloalkyl, halo, D, CN, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)OR^(a5), NR^(c5)S(O)R^(b5), NR^(c5)S(O)_(2R) ^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5),and S(O)₂NR^(c5)R^(d5); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl and 4-7membered heterocycloalkyl, are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R^(g); each R²¹ isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ alkylene, 5-10 memberedheteroaryl-C₁₋₃ alkylene, halo, D, CN, OR^(a4), SR^(a4), C(O)R^(b4),C(O)NR^(c4)R^(d4), C(O)OR^(a4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4),NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4),and S(O)₂NR^(c4)R^(d4); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R²²; each R²² isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7membered heterocycloalkyl, halo, D, CN, OR^(a6), SR^(a6), C(O)R^(b6),C(O)NR^(c6)R^(d6), C(O)OR^(a6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)OR^(a6), NR^(c6)S(O)R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6), S(O)₂R^(b6),and S(O)₂NR^(c6)R^(d6); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7membered heterocycloalkyl, are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R^(g); each R^(a1), R^(c1)and R^(d1) is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹¹; or any R^(c1) and R^(d1) attached to the same N atom,together with the N atom to which they are attached, form a 4-, 5-, 6-or 7-membered heterocycloalkyl group optionally substituted with 1, 2,3, or 4 substituents independently selected from R¹¹; each R^(b1) isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryland 5-10 membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl, are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R¹¹; each R^(e1)is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamoyl,di(C₁₋₆alkyl)carbamyl, amino sulfonyl, C₁₋₆ alkylaminosulfonyl anddi(C₁₋₆alkyl)aminosulfonyl; each R^(a2), R^(c2) and R^(d2), isindependently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl and 5-10 membered heteroaryl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R²¹; or anyR^(c2) and R^(d2) attached to the same N atom, together with the N atomto which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R²¹; each R^(b2) isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryland 5-10 membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R²¹; each R^(e2)is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamoyl, di(C₁₋₆alkyl)carbamyl, amino sulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl; each R^(a3), R^(c3) and R^(d3), is independentlyselected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 memberedheterocycloalkyl; wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 memberedheterocycloalkyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹²; or any R^(c3) and R^(d3)attached to the same N atom, together with the N atom to which they areattached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2 or 3 substituents independentlyselected from R¹²; each R^(b3) is independently selected from C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl;wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl, areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹²; each R^(a4), R^(c4) and R^(d4), isindependently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7membered heterocycloalkyl; wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7membered heterocycloalkyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R²²; or any R^(c3) andR^(d4) attached to the same N atom, together with the N atom to whichthey are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkylgroup optionally substituted with 1, 2 or 3 substituents independentlyselected from R²²; each R^(b4) is independently selected from C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl;wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²²; each R^(a5), R^(c5) and R^(d5), isindependently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyland C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g); each R^(b5) is independently selectedfrom C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; whereinsaid C₁₋₆ alkyl C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR^(g); each R^(a6), R^(c6) and R^(d6), is independently selected from H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR^(g); each R^(b6) is independently selected from C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl and C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R^(g); and each R^(g) isindependently selected from OH, NO₂, CN, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₂alkylene, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₁₋₃alkoxy-C₁₋₃ alkoxy, HO—C₁₋₃ alkoxy, HO—C₁₋₃ alkyl, cyano-C₁₋₃ alkyl,H₂N—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino, thio, C₁₋₆alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl, C₁₋₆alkylcarbamoyl, di(C₁₋₆alkyl)carbamyl, carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆alkoxycarbonyl, C₁₋₆ alkylcarbonylamino, C₁₋₆ alkylsulfonylamino,aminosulfonyl, C₁₋₆ alkylaminosulfonyl, di(C₁₋₆alkyl)aminosulfonyl,aminosulfonylamino, C₁₋₆ alkylaminosulfonylamino,di(C₁₋₆alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₆alkylaminocarbonylamino, and di(C₁₋₆ alkyl)aminocarbonylamino.
 2. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein Cy¹ is selected from phenyl, pyridinyl and pyrazolyl; whereinthe phenyl, pyridinyl, and pyrazolyl are each optionally substitutedwith 1, 2, 3 or 4 substituents independently selected from R¹⁰.
 3. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein Cy¹ is selected from phenyl, pyridin-3-yl and pyrazol-4-yl;wherein the phenyl, pyridin-3-yl, and pyrazol-4-yl are each optionallysubstituted with 1 substituent selected from R¹⁰.
 4. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein Cy¹ is5-6 membered heteroaryl optionally substituted with 1 or 2 substituentsselected from R¹⁰.
 5. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein Cy¹ is selected from pyrazol-4-yl andpyridin-3-yl; wherein the pyrazol-4-yl and pyridin-3-yl are eachoptionally substituted with 1 or 2 substituents selected from R¹⁰. 6.The compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R¹ is selected from halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C3-5cycloalkyl, 4-5 membered heterocycloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,C₁₋₃ alkoxy-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, C₁₋₆ alkylamino, and di(C₁₋₆alkyl)amino; wherein optionally one or more H atoms of the C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₅ cycloalkyl, 4-5 membered heterocycloalkyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, C₁₋₃ alkoxy-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, C₁₋₆alkylamino, and di(C₁₋₆alkyl)amino are replaced by one or more D atoms.7. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R¹ is selected from Cl, C₁₋₂ alkyl, C₁₋₂ haloalkyl,hydroxymethyl, C₁₋₂ alkoxy, C₁₋₂ haloalkoxy and C₁₋₂ alkylamino; whereinoptionally one or more H atoms of the C₁₋₂ alkyl, C₁₋₂ haloalkyl,hydroxymethyl, C₁₋₂ alkoxy, C₁₋₂ haloalkoxy and C₁₋₂ alkylamino arereplaced by one or more D atoms.
 8. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R¹ is selected fromCl, CH₃, OCH₃, OCD₃, OCH₂CH₃, OCHF₂, NHCH₃, CHF₂, and CH₂OH.
 9. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R¹ is OCH₃.
 10. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein each R² is independently selected fromC₁₋₆ alkyl, C₃₋₆ cycloalkyl, halo, and OR^(a2); wherein said C₁₋₆ alkyland C₃₋₆ cycloalkyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R²¹.
 11. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein two adjacentR² substituents on the phenyl ring, taken together with the atoms towhich they are attached, form a fused 5-membered cycloalkyl ring, or afused 5- or 6-membered heterocycloalkyl ring; wherein each fused 5- or6-membered heterocycloalkyl ring has at least one ring-forming carbonatom and 1 or 2 ring-forming O atoms; and wherein the fused 5-memberedcycloalkyl ring, and the fused 5- or 6-membered heterocycloalkyl ringare each optionally substituted with 1 or 2 substituents independentlyselected from R²¹.
 12. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein each R² is independently selected fromC₁₋₃ alkyl, C₁₋₃ haloalkyl, C₃₋₆ cycloalkyl, F, Cl, CN, and OR^(a2);wherein said C₁₋₃ alkyl, and C₃₋₆ cycloalkyl, are each optionallysubstituted with 1, 2 or 3 substituents independently selected from R²¹.13. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein each R² is independently selected from F, methyl,CH₂CN, CD₃, OH, OCH₃, and cyclopropyl.
 14. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein the R² substituents,taken together with the atoms to which they are attached, form a fusedcyclopentyl group, a fused tetrahydrofuranyl group, a fused 1,4-dioxanylgroup, or a fused tetrahydropyranyl group, each of which is optionallysubstituted with 1 or 2 substituents selected from R²¹.
 15. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein theR² substituents, taken together with the atoms to which they areattached, form a fused cyclopentyl group optionally substituted with 1or 2 substituents independently selected from D, OH, CN, CH₂OH, and F.16. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein the R² substituents, taken together with the atoms towhich they are attached, form a fused cyclopentyl group or a fusedcyclohexyl group; wherein the fused cyclopentyl group and the fusedcyclohexly group have at least one ring-forming carbon atom and eachoptionally have 1 or 2 ring-forming O atoms; and wherein the fusedcyclopentyl group and the fused cyclohexly group are each optionallysubstituted with 1 or 2 substituents independently selected from D, OH,CN, CH₂OH, and F.
 17. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein the R² substituents, taken togetherwith the atoms to which they are attached, form a fused cyclopentylgroup.
 18. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein n is selected from 0 and
 1. 19. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein n is 0.20. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein each R¹⁰ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-12 membered heterocycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, C₃₋₁₀ alkylene, 4-12 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 memberedheteroaryl-C₁₋₃ alkylene, halo, D, CN, OR^(a1), C(O)R^(b1);C(O)NR^(c1)R^(d1), C(O)OR^(a1); NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), andS(O)₂R^(b1); wherein said C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-12 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-12 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹.
 21. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein each R¹⁰ isindependently selected from C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₃₋₆ cycloalkyl,4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, 4-6 memberedheterocycloalkyl-C₁₋₂ alkylene, 5-6 membered heteroaryl-C₁₋₂ alkylene,halo, D, CN, C(O)NR^(c1)R^(d1), and NR^(c1)R^(d1); wherein the C₁₋₃alkyl, C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 memberedheteroaryl, 4-6 membered heterocycloalkyl-C₁₋₂ alkylene, and 5-6membered heteroaryl-C₁₋₂ alkylene are each optionally substituted with 1or 2 substituents independently selected from R¹¹.
 22. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein each R¹⁰is independently selected from C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₃₋₆cycloalkyl, 4-10 membered heterocycloalkyl, 5-6 membered heteroaryl, 4-6membered heterocycloalkyl-C₁₋₂ alkylene, 5-6 membered heteroaryl-C₁₋₂alkylene, halo, D, CN, OR^(a1), C(O)NR^(c1)R^(d1); and NR^(c1)R^(d1);wherein the C₁₋₃ alkyl, C₃₋₆ cycloalkyl, 4-10 membered heterocycloalkyl,5-6 membered heteroaryl, 4-6 membered heterocycloalkyl-C₁₋₂ alkylene,and 5-6 membered heteroaryl-C₁₋₂ alkylene are each optionallysubstituted with 1 or 2 substituents independently selected from R¹¹.23. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein each R¹⁰ is independently selected from C₁₋₂ alkyl,C₁₋₂ haloalkyl, F, Cl, D, CN, OR^(a1) and NR^(c1)R^(d1); wherein theC₁₋₂ alkyl is optionally substituted with 1 or 2 substituentsindependently selected from R¹¹.
 24. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein each R¹⁰ isindependently selected from methyl,(1-methyl-1H-1,2,4-triazol-5-yl)methyl, pyrrolidin-3-yl,pyrrolidin-1-yl, 1-ethylpyrrolidin-3-yl, 1-methylazetidin-3-yl,1-ethylazetidin-3-yl, 4-acetylpiperazin-1-yl, 3-cyanocyclobutyl,1-(dimethylcarbamoyl)piperidin-4-yl, 1-(methoxycarbonyl)piperidin-4-yl,1-(methoxycarbonyl)azetidin-3-yl, 1-acetylazetidin-3-yl,1-(methylsulfonyl)azetidin-3-yl, 1-(dimethylcarbamoyl)azetidin-3-yl,1-(cyclopropanecarbonyl)azetidin-3-yl, pyridin-4-ylmethyl,2-morpholinoethyl, cyclopropyl, 2-cyanoethyl, 2-hydroxyethyl,pyridin-4-yl, 4-hydroxycyclohexyl, 4-methylpiperazin-1-yl,4-ethylpiperazin-1-yl, morpholino, 4-methyl-3-oxopiperazin-1-yl,4-hydroxypiperidin-1-yl, (R)-3,4-dimethylpiperazin-1-yl,(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl,4-(dimethylcarbamoyl)piperidin-1-yl, 4-carboxy-4-methylpiperidin-1-yl,(1S,4S)-4-acetamidocyclohexyl, 2,4-dimethylpiperazin-1-yl,4-(ethylcarbamoyl)piperazin-1-yl, 4-carbamoylpiperazin-1-yl,4-isopropylpiperazin-1-yl, 4-ethylpiperazin-1-yl,2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-8-yl, pyridin-2-ylmethyl,1-acetylpiperidin-4-yl), 1-(methoxycarbonyl)piperidin-4-yl,(tetrahydrofuran-3-yl)oxy, 1-methyl-5-oxopyrrolidin-3-yl,1-(2-hydroxypropanoyl)piperidin-4-yl, 1-(2-hydroxyacetyl)piperidin-4-yl,4-carboxycyclohexyl, 3-amino-4-fluoropyrrolidin-1-yl,(7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl,(7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl,4-imino-4-oxo-4λ⁶-piperazin-1-yl,(2-hydroxy-N-methylacetamido)pyrrolidin-1-yl,4-(2-hydroxyethyl)piperazin-1-yl, 2-methoxyethoxy,(tetrahydro-2H-pyran-4-yl)oxy, cyclopropyl, and3-(2-hydroxy-N-methylacetamido)azetidin-1-yl,1-(2-hydroxyacetyl)pyrrolidin-3-yl, 1-acetylpiperidin-3-yl,1-(3′-pyrrolidin-2′-one)pyrrolidin-3-yl,1-(1′-methyl-(3′-pyrrolidin-2′-one))pyrrolidin-3-yl,1-(2-propanamide)pyrrolidin-3-yl, 1-(methyl-L-prolyl)piperidin-4-yl,1-(4-methylmorpholin-3-yl)pyrrolidin-3-yl, 3-cyanocyclobut-1-yl,1-(hydroxymethylcarbonyl)azetidin-3-yl,1-(2-(dimethylamino)ethanecarbonyl)azetidin-3-yl,1-(dimethylamino-methyl-acetyl)azetidin-3-yl,1-((1-methylazetidin-2-yl)carbonyl)azetidin-3-yl,1-(2-(4-methylpiperazin-1-yl)ethan-1-one)azetidin-3-yl,1-(2-(4-hydroxypiperazin-1-yl)ethan-1-one)azetidin-3-yl,1-((1-methylazetidin-2-yl)carbonyl)azetidin-3-yl,1-(hydroxy-methyl-acetyl)azetidin-3-yl,1-((trans)-3-hydroxycyclobutylcarbonyl)azetidin-3-yl,1-((cis)-3-hydroxycyclobutylcarbonyl)azetidin-3-yl,1-((4-methylmorpholin-3-yl)carbonyl)azetidin-3-yl,1-(hydroxyl-acetyl)pyrrolidin-3-yl,1-((tetrahydrofuran-2-yl)carbonyl)azetidin-3-yl,1-((tetrahydrofuran-3-yl)carbonyl)azetidin-3-yl,1-(hydroxy-methyl-acetyl)pyrrolidin-3-yl,1-(3-hydroxybutanoyl)azetidin-3-yl,1-((−3-hydroxy-3-methylcyclobutyl)carbonyl)azetidin-3-yl,1-(4-methylmorpholin-3-yl)carbonyl)pyrrolidin-3-yl,1-((hydroxymethyl)cyclobutylcarbonyl)azetidin-3-yl,1-((1-ethylazetidin-2-yl)carbonyl)azetidin-3-yl,1-((1-(2-fluoroethyl)azetidin-2-yl)carbonyl)azetidin-3-yl,1-((1-isopropylazetidin-2-yl)carbonyl)azetidin-3-yl,1-((1-(2-fluoroethyl)azetidin-2-yl)carbonyl)pyrrolidin-3-yl,1-((trans)-3-hydroxycyclobutylcarbonyl)pyrrolidin-3-yl,1-((cis)-3-hydroxycyclobutylcarbonyl)pyrrolidin-3-yl,1-((3-hydroxy-3-methylcyclobutyl)carbonyl)pyrrolidin-3-yl,1-(2-methoxyethan-1-one)azetidin-3-yl,1-(2-(dimethylamino)-2-methylpropan-1-one)azetidin-3-yl,1-((cyclopropane-1-carbonitrile)carbonyl)azetidin-3-yl,1-((ethan-1-ol)sulfonyl)azetidin-3-yl,1-((N,N-dimethylethan-1-amine)sulfonyl)azetidin-3-yl,1-((2-methoxyethyl)carboxylate)azetidin-3-yl,1-((3-methoxycyclobutyl)carbonyl)azetidin-3-yl,3-(2-hydroxy-N-methylacetamide)cyclopentyl,3-(2-hydroxypropanamid)cyclopentyl, 3-(2-hydroxyacetamide)cyclopentyl,3-(2-hydroxyethyl)-3-azabicyclo[3.1.0]hexan-1-yl,(4-hydroxypiperidin-1-yl)methyl,(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl, 1-(morpholin-4-yl)ethyl,(5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine-7-yl)methyl,1-(2-hydroxyethyl)piperidin-4-yl-4-carbonitrile,1-(2-hydroxyacetyl)piperidin-4-yl-4-carbonitrile,2-methoxyethylpiperazin-1-yl,1-(tetrahydro-2H-pyran-4-carbonyl)piperidin-4-yl-4-d,1-(2-methoxyacetyl)pyrrolidin-3-yl,1-(tetrahydrofuran-2-carbonyl)pyrrolidin-3-yl,3-(2-hydroxy-N-methylacetamide)azetidin-1-yl,1-((tetrahydrofuran-2-yl)carbonyl)azetidin-3-yl,1-((1-methylpiperidin-2-yl)carbonyl)azetidin-3-yl,1-(2-(dimethylamino)ethan-1-one)azetidin-3-yl,1-(3-hydroxypropan-1-one)azetidin-3-yl,1-(2-hydroxyethan-1-one)azetidin-3-yl,1-(2-hydroxypropan-1-one)azetidin-3-yl,1-(2-hydroxy-N-methylacetamide)cyclobut-3-yl,1-(2-hydroxyethan-1-one)-3-d-azetidin-3-yl, 1-carboxylatepiperidin-4-yl,1-(morpholine-4-carbonyl)piperidin-4-yl, 1-acetylpyrrolidin-3-yl,1-(morpholine-4-carbonyl)pyrrolidin-3-yl, cyanomethyl,1-propanenitrile-azetidin-3-yl,1-(2-methoxy-N-methylacetamide)cyclobut-3-yl,1-(3-hydroxy-N-methylpropanamide)cyclobut-3-yl,1-(2-hydroxy-N-methylpropanamide)cyclobut-3-yl,1-(2-hydroxyethan-1-one)azabicyclo[3.1.0]hexan-3-yl,1-((4-methylmorpholin-3-yl)carbonyl)azabicyclo[3.1.0]hexan-3-yl,1-(tetrahydro-2H-pyran-4-yl)azabicyclo[3.1.0]hexan-3-yl,1-(ethan-1-ol)azabicyclo[3.1.0]hexan-3-yl,1-(4-methylmorpholine-3-carbonyl)-3-carbonitrile-pyrrolidin-3-yl,1-(4-methylmorpholine-3-carbonyl)-4-carbonitrile-piperdin-4-yl,1-(2-hydroxyacetyl)-3-carbonitrile-pyrrolidin-3-yl,(1,3-dimethylpiperazin-4-yl-2-one)methyl, and(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl.
 25. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein each R¹¹ isindependently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, halo, D, CN, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3),S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3); wherein said C₁₋₆ alkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10membered heteroaryl, are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹².
 26. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein each R¹¹ isindependently selected from C₁₋₃ alkyl, C₁₋₃ haloalkyl, C3-4 cycloalkyl,5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, halo, D, CN,OR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), NR^(c3)R^(d3),NR^(c3)C(O)R^(b3), S(O)₂R^(b3); and NR^(c3)S(O)₂R^(b3), wherein saidC₁₋₃ alkyl, C3-4 cycloalkyl, 5-6 membered heteroaryl, and 4-6 memberedheterocycloalkyl are each optionally substituted with 1 substituentselected from R¹².
 27. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein each R¹¹ is independently selected fromhalo, C₁₋₂ alkyl, CN, OR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)OR^(a3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), S(O)₂R^(b3),1-methyl-pyrrolidin-3-yl-2-one, pyrrolidin-3-yl-2-one, 2-propanamide,NR^(c3)S(O)₂R^(b3), D, and tetrahydropyran-4-yl, wherein said C₁₋₂ alkylis optionally substituted with OR^(a5).
 28. The compound of claim 1, ora pharmaceutically acceptable salt thereof, wherein each R¹¹ isindependently selected from C₁₋₃ alkyl, 4-10 membered heterocycloalkyl,F, D, CN, OR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)S(O)₂R^(b3), and S(O)₂R^(b3);wherein said C₁₋₃ alkyl, and 4-10 membered heterocycloalkyl, are eachoptionally substituted with 1 or 2 substituents independently selectedfrom R¹².
 29. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein each R¹¹ is independently selected from D, methyl,ethyl, isopropyl, CN, OH, oxo, (1-methyl-1H-1,2,4-triazol-5-yl)methyl,CH₂CH₂OH, C(O)CH₃, C(O)N(CH₃)₂, C(O)NH₂, C(O)NHCH₂CH₃,C(O)CH₂CH₂N(CH₃)₂, C(O)CH(CH₃)N(CH₃)₂, C(O)OCH₃, C(O)CH₂OH,CH(CH₃)C(O)NH₂, C(O)OH, NHC(O)CH₃, S(O)₂CH₃, cyclopropanecarbonyl,pyridin-4-yl, pyridin-2-yl, morpholino, 2-hydroxypropanoyl,2-hydroxyacetyl, 2-hydroxyethyl, F, NH₂, N(CH₃)C(O)CH₂OH,3′-pyrrolidin-2′-one, methyl-3′-pyrrolidin-2′-one, 1-methyl-prolyl,(4-methylmorpholin-3-yl)methyl-1-one,(1-methylazetidin-2-yl)methyl-1-one,2-(4-methylpiperazin-1-yl)ethyl-1-one,2-(4-hydroxypiperidin-1-yl)ethyl-1-one, 2-hydroxypropyl-1-one,(trans)-3-hydroxycyclobutyl)methyl-1-one,(cis)-3-hydroxycyclobutyl)methyl-1-one,(4-methylmorpholin-3-yl)methyl-1-one,(tetrahydrofuran-2-yl)methyl-1-one, 2-hydroxypropyl-1-one,3-hydroxybutyl-1-one, 3-hydroxy-3-methylcyclobutyl)methyl-1-one,(hydroxymethyl)cyclobutyl)methyl-one,(1-ethylazetidin-2-yl)methyl-1-one,(2-fluoroethyl)azetidin-2-yl)methyl-1-one,(1-isopropylazetidin-2-yl)methyl-1-one, 2-methoxyethyl-1-one,2-(dimethylamino)-2-methylpropyl-1-one,(cyclopropane-1-carbonitrile)methyl-1-one, S(O)₂CH₂CH₂OH,S(O)₂CH₂CH₂N(CH₃)₂, 2-methoxyethyl-carboxyl, N-methylmethanesulfonamido,2-hydroxy-N-methylacetamido, 2-hydroxypropanamido,tetrahydro-2H-pyran-4-methyl-1-one, 2-methoxyacetyl,2-hydroxy-N-methylacetamido, tetrahydrofuran-2-methyl-1-one,(1-methylpiperidin-2-yl)methyl-1-one, 2-(dimethylamino)ethyl-1-one,3-hydroxypropyl-1-one, methoxymethyl-carboxyl, morpholine-4-carbonyl,propylnitrile, 2-methoxy-N-methylacetamido,3-hydroxy-N-methylpropanamido, 2-hydroxy-N-methylpropanamido,tetrahydro-2H-pyran-4-yl, and 1,3-dimethylpiperazinyl-2-one.
 30. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein each R^(b3) is independently selected from C₁₋₃ alkyl, C₁₋₃haloalkyl, C₃₋₆ cycloalkyl, and 4-6 membered heterocycloalkyl; whereinsaid C₁₋₃ alkyl C3-6 cycloalkyl, and 4-6 membered heterocycloalkyl, areeach optionally substituted with 1 or 2 substituents independentlyselected from R¹².
 31. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein any R^(c3) and R^(d3) attached to thesame N atom, together with the N atom to which they are attached, form a4-, 5- or 6-membered heterocycloalkyl group optionally substituted with1 or 2 substituents independently selected from R¹².
 32. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein each R¹²is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆cycloalkyl, 4-7 membered heterocycloalkyl, halo, D, CN, OR^(a5),SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), NR^(c5)R^(d5),NR^(c5)C(O)R^(b5), S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5); wherein saidC₁₋₆ alkyl, C₃₋₆ cycloalkyl, and 4-7 membered heterocycloalkyl, are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g).
 33. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein each R¹² is independently selected fromC₁₋₃ alkyl, C₁₋₃ haloalkyl, C₃₋₆ cycloalkyl, 4-7 memberedheterocycloalkyl, F, Cl, D, CN, OR^(a5)C(O)R^(b5), C(O)NR^(c5)R^(d5),and NR^(c5)R^(d5); wherein said C₁₋₃ alkyl, C3-6 cycloalkyl, and 4-7membered heterocycloalkyl, are each optionally substituted with 1substituent independently selected from R^(g).
 34. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein each R²¹ isindependently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, D, CN,OR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), NR^(c4)R^(d4), andS(O)₂R^(b4); wherein said C₁₋₆ alkyl is optionally substituted with 1,2, or 3 substituents independently selected from R²².
 35. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein eachR²¹ is independently selected from C₁₋₃ alkyl, halo, D, CN, and OR^(a4);wherein said C₁₋₃ alkyl, is optionally substituted with 1 or 2substituents independently selected from R²².
 36. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein each R²¹ isindependently selected from C₁₋₃ alkyl, F, Cl, D, CN, and OR^(a4);wherein said C₁₋₃ alkyl, is optionally substituted with 1 or 2substituents independently selected from R²².
 37. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein each R²² isindependently selected from halo, D, CN, and OR^(a6).
 38. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein eachR²² is independently selected from F, Cl, D, CN, and OR^(a6).
 39. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R²² is OR^(a6).
 40. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein each R^(g) isindependently selected from OH, CN, F, Cl, alkyl, and haloalkyl.
 41. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,having Formula IIb:

or a pharmaceutically acceptable salt thereof.
 42. The compound of claim1, or a pharmaceutically acceptable salt thereof, having Formula IIIa:

or a pharmaceutically acceptable salt thereof.
 43. The compound of claim1, or a pharmaceutically acceptable salt thereof, having Formula IIIb:

or a pharmaceutically acceptable salt thereof.
 44. The compound of claim1, or a pharmaceutically acceptable salt thereof, having Formula IIIc:

or a pharmaceutically acceptable salt thereof.
 45. The compound of claim1, or a pharmaceutically acceptable salt thereof, having Formula IVa:

or a pharmaceutically acceptable salt thereof.
 46. The compound of claim1, or a pharmaceutically acceptable salt thereof, having Formula Va:

or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, or 2.47. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein: Cy¹ is selected from phenyl, pyridinyl and pyrazolyl;wherein the phenyl pyridinyl and pyrazolyl are each optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR¹⁰; R¹ is selected from halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C3-5cycloalkyl, 4-5 membered heterocycloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,C₁₋₃ alkoxy-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, C₁₋₆ alkylamino, and di(C₁₋₆alkyl)amino; wherein any of the H atoms of the C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₅ cycloalkyl, 4-5 membered heterocycloalkyl, C₁₋₆ alkoxy,C₁₋₆ haloalkoxy, C₁₋₃ alkoxy-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, C₁₋₆ alkylamino,and di(C₁₋₆ alkyl)amino can be replaced by D atoms; each R² and R³ areindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆ haloalkyl,C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl, halo, CN, OR^(a2),C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), NR^(c2)R^(d2), andS(O)₂R^(b2); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl, and4-6 membered heterocycloalkyl are each optionally substituted with 1, 2,3, or 4 substituents independently selected from R²¹; or two adjacent R²substituents on the phenyl ring, taken together with the atoms to whichthey are attached, form a fused 5- or 6-membered cycloalkyl ring, or afused 5- or 6-membered heterocycloalkyl ring; wherein each fused 5- or6-membered heterocycloalkyl ring has at least one ring-forming carbonatom and 1 or 2 ring-forming heteroatoms independently selected from Oand N; wherein a ring-forming carbon atom of each fused 5- or 6-memberedheterocycloalkyl ring is optionally substituted by oxo to form acarbonyl group; and wherein the fused 5- or 6-membered cycloalkyl ring,and the fused 5- or 6-membered heterocycloalkyl ring are each optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR²¹; n is selected from 0 and 1; each R¹⁰ is independently selected fromC₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-12 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-12 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, OR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), (and S(O)₂R^(b1); wherein said C₁₋₆alkyl, C₃₋₁₀ cycloalkyl, 4-12 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-12 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R¹¹; each R¹¹ isindependently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, halo, D, CN, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3),S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3); wherein said C₁₋₆ alkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10membered heteroaryl, are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹²; each R¹² is independentlyselected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, 4-7 memberedheterocycloalkyl, halo, D, CN, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5); wherein said C₁₋₆ alkyl, C₃₋₆cycloalkyl, and 4-7 membered heterocycloalkyl, are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR^(g); each R²¹ is independently selected from C₁₋₆ alkyl, C₁₋₆haloalkyl, halo, D, CN, C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4),NR^(c4)R^(d4), and S(O)₂R^(b4); wherein said C₁₋₆ alkyl, is optionallysubstituted with 1, 2, or 3 substituents independently selected fromR²²; each R²² is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, D, CN, OR^(a6), and NR^(c6)R^(d6); wherein said C₁₋₆ alkyl, isoptionally substituted with 1 or 2 substituents independently selectedfrom R^(g); each R^(a1), R^(c1) and R^(d1) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, and 4-10 memberedheterocycloalkyl; wherein said C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, and 4-10membered heterocycloalkyl, are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹¹; or any R^(c1) andR^(d1) attached to the same N atom, together with the N atom to whichthey are attached, form a 4-, 5-, or 6-membered heterocycloalkyl groupoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹¹; each R^(b1) is independently selected from C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, and 4-10 memberedheterocycloalkyl, wherein said C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, and 4-10membered heterocycloalkyl, are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹¹; each 10², R^(c2) andR^(d2), is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, and 4-10 membered heterocycloalkyl; wherein said C₁₋₆alkyl, C₃₋₁₀ cycloalkyl, and 4-10 membered heterocycloalkyl, are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R²¹; or any R^(c2) and R^(d2) attached to the same N atom,together with the N atom to which they are attached, form a 4-, 5-, or6-membered heterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R²¹; each R^(b2) isindependently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, and 4-10 membered heterocycloalkyl; wherein said C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl, and 4-10 membered heterocycloalkyl, are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R²¹; each 10³, R^(c3) and R^(d3), is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, and 4-7membered heterocycloalkyl; wherein said C₁₋₆ alkyl C₃₋₆ cycloalkyl, and4-7 membered heterocycloalkyl are each optionally substituted with 1, 2,3, or 4 substituents independently selected from R¹²; or any R^(c3) andR^(d3) attached to the same N atom, together with the N atom to whichthey are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkylgroup optionally substituted with 1, 2 or 3 substituents independentlyselected from R¹²; each R^(b3) is independently selected from C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, and 4-7 memberedheterocycloalkyl; wherein said C₁₋₆ alkyl C₃₋₆ cycloalkyl, and 4-7membered heterocycloalkyl, are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹²; each R^(a4), R^(c4)and R^(d4), is independently selected from H, C₁₋₆ alkyl, and C₁₋₆haloalkyl; wherein said C₁₋₆ alkyl is optionally substituted with 1, 2,3, or 4 substituents independently selected from R²²; each R^(b4) isindependently selected from C₁₋₆ alkyl, and C₁₋₆ haloalkyl; wherein saidC₁₋₆ alkyl is optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²²; each R^(a5), R^(c5) and R^(d5), isindependently selected from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl; whereinsaid C₁₋₆ alkyl, is optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g); each R^(b5) isindependently selected from C₁₋₆ alkyl, and C₁₋₆ haloalkyl; wherein saidC₁₋₆ alkyl is optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g); each R^(a6), R^(c6) and R^(d6), isindependently selected from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl; whereinsaid C₁₋₆ alkyl, is optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g); each R^(b6) isindependently selected from C₁₋₆ alkyl, and C₁₋₆ haloalkyl; wherein saidC₁₋₆ alkyl, is optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g); and each R^(g) is independentlyselected from OH, CN, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₃ alkoxy-C₁₋₃ alkyl, HO—C₁₋₃ alkyl,cyano-C₁₋₃ alkyl, H₂N—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, di(C₁₋₆alkyl)amino, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, carboxy, C₁₋₆alkylcarbonyl, C₁₋₆ alkoxycarbonyl, and C₁₋₆ alkylcarbonylamino.
 48. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein: or a pharmaceutically acceptable salt thereof, wherein: Cy¹ isselected from phenyl, pyridine-3-yl and pyrazol-4-yl; wherein thephenyl, pyridine-3-yl and pyrazol-4-yl of Cy¹ are each optionallysubstituted with 1 substituent selected from R¹⁰; R¹ is selected fromCl, C₁₋₃ alkyl, C₁₋₃ haloalkyl, cyclopropyl, azedinyl, hydroxymethyl,C₁₋₃ alkoxy, C₁₋₃ haloalkoxy and C₁₋₃ alkylamino; wherein the C₁₋₃alkyl, C₁₋₃ haloalkyl, cyclopropyl, azedinyl, hydroxymethyl, C₁₋₃alkoxy, C₁₋₃ haloalkoxy and C₁₋₃ alkylamino are each optionallysubstituted with 1, 2, 3, 4, 5, 6, or 7 deuteriums; each R² isindependently selected from C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₃₋₆ cycloalkyl,F, Cl, CN, and OR^(a2); wherein said C₁₋₃ alkyl, and C₃₋₆ cycloalkyl,are each optionally substituted with 1, 2 or 3 substituentsindependently selected from R²¹; or the R² substituents on the phenylring, taken together with the atoms to which they are attached, form afused 5- or 6-membered cycloalkyl ring, or a fused 5- or 6-memberedheterocycloalkyl ring; wherein each fused 5- or 6-memberedheterocycloalkyl ring has at least one ring-forming carbon atom and 1 or2 ring-forming O atoms; and wherein the fused 5- or 6-memberedcycloalkyl ring, and the fused 5- or 6-membered heterocycloalkyl ringare each optionally substituted with 1 or 2 substituents independentlyselected from R²¹; n is 0; each R¹⁰ is independently selected from C₁₋₃alkyl, C₁₋₃ haloalkyl, C₃₋₆ cycloalkyl, 4-10 membered heterocycloalkyl,5-6 membered heteroaryl, 4-10 membered heterocycloalkyl-C₁₋₂ alkylene,5-6 membered heteroaryl-C₁₋₂ alkylene, F, Cl, D, CN, OR^(a1),C(O)NR^(c1)R^(d1), and NR^(c1)R^(d1); wherein said C₁₋₃ alkyl, C₃₋₆cycloalkyl, 4-10 membered heterocycloalkyl, 5-6 membered heteroaryl,4-10 membered heterocycloalkyl-C₁₋₂ alkylene, and 5-6 memberedheteroaryl-C₁₋₂ alkylene are each optionally substituted with 1 or 2substituents independently selected from R¹¹; each R¹¹ is independentlyselected from C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₃₋₆ cycloalkyl, 4-10 memberedheterocycloalkyl, 5-6 membered heteroaryl, F, Cl, D, CN, OR^(a3),C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), NR^(c3)R^(d3),NR^(c3)C(O)R^(b3), NR^(c3)S(O)₂R^(b3), S(O)₂R^(b3), andS(O)₂NR^(c3)R^(d3); wherein said C₁₋₃ alkyl, C₃₋₆ cycloalkyl, 4-10membered heterocycloalkyl, and 5-6 membered heteroaryl, are eachoptionally substituted with 1 or 2 substituents independently selectedfrom R¹²; each R¹² is independently selected from C₁₋₃ alkyl, C₁₋₃haloalkyl, C₃₋₆ cycloalkyl, 4-7 membered heterocycloalkyl, F, Cl, D, CN,OR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), and NR^(c5)R^(d5); wherein saidC₁₋₃ alkyl, C₃₋₆ cycloalkyl, and 4-7 membered heterocycloalkyl, are eachoptionally substituted with 1 substituent independently selected fromR^(g); R²¹ is independently selected from C₁₋₃ alkyl, F, Cl, D, CN, andOR^(a4); wherein said C₁₋₃ alkyl, is optionally substituted with 1 or 2substituents independently selected from R²²; each R²² is independentlyselected from F, Cl, D, CN, and OR^(a6); each R^(a1), R^(c1) and R^(d1)is independently selected from H, C₁₋₃ alkyl, C₁₋₃ haloalkyl, and 4-6membered heterocycloalkyl; wherein said C₁₋₃ alkyl, and 4-6 memberedheterocycloalkyl, are each optionally substituted with 1 substituentindependently selected from R¹¹; each R^(a2) is independently selectedfrom H, C₁₋₃ alkyl, and C₁₋₃ haloalkyl; each R^(a3), R^(c3) and R^(d3),is independently selected from H, C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₃₋₆cycloalkyl, and 4-6 membered heterocycloalkyl; wherein said C₁₋₃ alkylC₃₋₆ cycloalkyl, and 4-6 membered heterocycloalkyl are each optionallysubstituted with 1 or 2 substituents independently selected from R¹²; orany R^(c3) and R^(d3) attached to the same N atom, together with the Natom to which they are attached, form a 4-, 5- or 6-memberedheterocycloalkyl group optionally substituted with 1 or 2 substituentsindependently selected from R¹²; each R^(b3) is independently selectedfrom C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₃₋₆ cycloalkyl, and 4-6 memberedheterocycloalkyl; wherein said C₁₋₃ alkyl C₃₋₆ cycloalkyl, and 4-6membered heterocycloalkyl, are each optionally substituted with 1 or 2substituents independently selected from R¹²; each R^(a4) isindependently selected from H, C₁₋₃ alkyl, and C₁₋₃ haloalkyl; eachR^(a5), R^(c5) and R^(d5), is independently selected from H, C₁₋₃ alkyl,and C₁₋₃ haloalkyl; wherein said C₁₋₃ alkyl, is optionally substitutedwith 1 substituent independently selected from R^(g); each R^(b5) isindependently selected from C₁₋₃ alkyl, and C₁₋₃ haloalkyl; wherein saidC₁₋₃ alkyl is optionally substituted with 1 substituents independentlyselected from R^(g); each R^(ab) is independently selected from H, andC₁₋₃ alkyl; and each R^(g) is independently selected from OH, CN, F, Cl,C₁₋₃ alkyl, and C₁₋₃ haloalkyl.
 49. The compound of claim 1, selectedfrom:5-(2,3-dimethylphenyl)-6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine;5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine;5-(2,3-dimethylphenyl)-6-methoxy-3-(1-((1-methyl-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine;5-(2,3-dihydrobenzofuran-7-yl)-6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine;2-(3-(6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2-methylphenyl)acetonitrile;1-(4-(5-(6-(difluoromethoxy)-5-(2,3-dimethylphenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperazin-1-yl)ethan-1-one;4-(6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-1-ol;4-(6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile;4-(6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-2-ol;(4-(6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-1-yl)methanol;2-fluoro-4-(6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-1-ol;5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-3-(1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine;5-(2,3-dihydro-1H-inden-4-yl)-3-(1-(1-ethylpyrrolidin-3-yl)-1H-pyrazol-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine;3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)cyclobutanecarbonitrile;5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-3-(1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine;5-(2,3-dihydro-1H-inden-4-yl)-3-(1-(1-ethylazetidin-3-yl)-1H-pyrazol-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine;4-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)-N,N-dimethylpiperidine-1-carboxamide;methyl4-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;methyl3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate;1-(3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)ethan-1-one;5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-3-(1-(1-(methylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine;3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)-N,N-dimethylazetidine-1-carboxamide;cyclopropyl(3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)methanone;5-(2,3-dihydro-1H-inden-4-yl)-6-ethoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine;5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-3-(1-(pyridin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine;4-(2-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)ethyl)morpholine;3-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine;3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)propanenitrile;2-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)ethan-1-ol;5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-3-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine;(trans)-4-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)cyclohexan-1-ol;5-(2,3-dimethylphenyl)-N-methyl-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-6-amine;6-(difluoromethyl)-5-(2,3-dihydro-1H-inden-4-yl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine;(5-(2,3-dihydro-1H-inden-4-yl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-6-yl)methanol;5-(2,3-dihydro-1H-inden-4-yl)-N-methyl-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-6-amine;(5-(2,3-dimethylphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-6-yl)methanol;4-(6-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-2-ol;5-(2,3-dimethylphenyl)-6-methyl-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine;5-(2,3-dimethylphenyl)-6-methoxy-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine;5-(2,3-dimethylphenyl)-3-(6-(4-ethylpiperazin-1-yl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine;1-(4-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrzolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperazin-1-yl)ethan-1-one;4-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)morpholine;4-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-1-methylpiperazin-2-one;1-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidin-4-ol;(R)-5-(2,3-dimethylphenyl)-3-(6-(3,4-dimethylpiperazin-1-yl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine;5-(2,3-dimethylphenyl)-6-(methoxy-d3)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine;5-(2,3-dimethylphenyl)-6-methoxy-3-(6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine;1-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-N,N-dimethylpiperidine-4-carboxamide;1-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-4-methylpiperidine-4-carboxylicacid;3-(4-(5-(2-fluoro-3-methylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)-N,N-dimethylazetidine-1-carboxamide;N-((cis)-4-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)cyclohexyl)acetamide;5-(2,3-dihydro-1H-inden-4-yl)-3-(6-(2,4-dimethylpiperazin-1-yl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine;2-(3-(3-(6-(4-acetylpiperazin-1-yl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2-methylphenyl)acetonitrile;2-(3-(6-methoxy-3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2-methylphenyl)acetonitrile;5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-3-(6-(pyrrolidin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine;4-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)morpholine;4-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-N-ethylpiperazine-1-carboxamide;4-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperazine-1-carboxamide;1-(4-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)phenyl)piperazin-1-yl)ethan-1-one;5-(2,3-dihydro-1H-inden-4-yl)-3-(4-(4-isopropylpiperazin-1-yl)phenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine;5-(2,3-dihydro-1H-inden-4-yl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine;1-(4-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperazin-1-yl)ethan-1-one;8-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one;5-(2,3-dimethylphenyl)-6-methoxy-3-(1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine;3-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine;6-methoxy-5-(2-methyl-3-(methyl-d3)phenyl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine;1-(4-(4-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethan-1-one;methyl4-(4-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;methyl3-(4-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate;and3-(4-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)-N,N-dimethylazetidine-1-carboxamide;or a pharmaceutically acceptable salt of any of the aforementioned. 50.The compound of claim 1, selected from:2-fluoro-4-(6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-1-ol;5-(2,3-dimethylphenyl)-6-methoxy-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine;4-(6-methoxy-3-(6-((tetrahydrofuran-3-yl)oxy)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-2-ol;4-(6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)2,3-dihydro-1H-inden-2-d-2-ol;4-(6-methoxy-3-(6-(1-methyl-5-oxopyrrolidin-3-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile;(S)-1-(4-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidin-1-yl)-2-hydroxypropan-1-one;1-(4-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidin-1-yl)-2-hydroxyethan-1-one;4-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclohexane-1-carboxylicacid;(3S,4R)-1-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-4-fluoropyrrolidin-3-amine;(2S)-1-(4-(5-(5-(2-fluoro-2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidin-1-yl)-2-hydroxypropan-1-one;1-(4-(5-(5-(2-fluoro-2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidin-1-yl)-2-hydroxyethan-1-one;(7R,8aS)-2-(5-(5-(2-fluoro-2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol;5-(2-fluoro-2,3-dihydro-1H-inden-4-yl)-6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine;(7S,8aR)-2-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol;4-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-1-imino-1λ⁶-thiomorpholine1-oxide;(7R,8aS)-2-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol;(S)—N-(1-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)pyrrolidin-3-yl)-2-hydroxy-N-methylacetamide;2-(3-(3-(6-(4-(2-hydroxyethyl)piperazin-1-yl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2-methylphenyl)acetonitrile;(7R,8aS)-2-(5-(6-methoxy-5-(3-methoxy-2-methylphenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol;(7R,8aS)-2-(5-(5-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol;(7R,8aS)-2-(5-(5-(2-cyclopropylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol;(7R,8aS)-2-(5-(5-(chroman-5-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol;(7R,8aS)-2-(5-(5-(2-fluoro-3-methylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol;4-(6-methoxy-3-(6-(2-methoxyethoxy)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-2-ol;4-(6-methoxy-3-(6-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-2-ol;4-(3-(6-cyclopropylpyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-2-ol;andN-(1-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-3-yl)-2-hydroxy-N-methylacetamide;or a pharmaceutically acceptable salt of any of the aforementioned. 51.The compound of claim 1, selected from:1-(4-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidin-1-yl)ethan-1-one;1-(4-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidin-1-yl)-2-hydroxyethan-1-one;1-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)pyrrolidin-1-yl)-2-hydroxyethan-1-one(Peak 1);1-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)pyrrolidin-1-yl)-2-hydroxyethan-1-one(Peak 2);1-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)pyrrolidin-1-yl)ethan-1-one(Peak 1);1-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)pyrrolidin-1-yl)ethan-1-one(Peak 2);3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-[1,3′-bipyrrolidin]-2′-one(Peak 1);3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-1′-methyl-[1,3′-bipyrrolidin]-2′-one(Peak 1);2-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)pyrrolidin-1-yl)propanamide(Peak 1);5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-3-(6-(1-(methyl-L-prolyl)piperidin-4-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine;(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)pyrrolidin-1-yl)((R)-4-methylmorpholin-3-yl)methanone(Peak 2);4-(6-Methoxy-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile;4-(3-(1-(3-Cyanocyclobutyl)-1H-pyrazol-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile;4-(3-(1-(1-Acetylpiperidin-4-yl)-1H-pyrazol-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile;4-(3-(6-(4-Hydroxycyclohexyl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile;4-(3-(6-(4-(2-Hydroxyethyl)piperazin-1-yl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile;4-(3-(6-(1-(2-Hydroxyacetyl)piperidin-4-yl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile;1-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-2-hydroxyethan-1-one;1-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-3-(dimethylamino)propan-1-one;(S)-1-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-2-(dimethylamino)propan-1-one;(S)-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(1-methylazetidin-2-yl)methanone;1-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-2-(4-methylpiperazin-1-yl)ethan-1-one;1-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-2-(4-hydroxypiperidin-1-yl)ethan-1-one;(R)-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(1-methylazetidin-2-yl)methanone;(R)-1-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-2-hydroxypropan-1-one;(S)-1-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-2-hydroxypropan-1-one;(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)((trans)-3-hydroxycyclobutyl)methanone;(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)((cis)-3-hydroxycyclobutyl)methanone;(R)-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(4-methylmorpholin-3-yl)methanone;(S)-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(4-methylmorpholin-3-yl)methanone;(S)-1-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)-2-hydroxyethan-1-one;(S)-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(tetrahydrofuran-2-yl)methanone;(S)-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(tetrahydrofuran-3-yl)methanone;(R)-1-((S)-3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)-2-hydroxypropan-1-one;(S)-1-((S)-3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)-2-hydroxypropan-1-one;(R)-1-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-3-hydroxybutan-1-one;(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)((1r,3r)-3-hydroxy-3-methylcyclobutyl)methanone;(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)((1s,3s)-3-hydroxy-3-methylcyclobutyl)methanone;((R)-3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)((S)-4-methylmorpholin-3-yl)methanone;((S)-3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)((R)-4-methylmorpholin-3-yl)methanone;(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(1-(hydroxymethyl)cyclobutyl)methanone;(S)-(3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(1-ethylazetidin-2-yl)methanone;(S)-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(1-(2-fluoroethyl)azetidin-2-yl)methanone;(S)-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(1-isopropylazetidin-2-yl)methanone;((S)-3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)((S)-1-(2-fluoroethyl)azetidin-2-yl)methanone;((S)-3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)((trans)-3-hydroxycyclobutyl)methanone;((S)-3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)((cis)-3-hydroxycyclobutyl)methanone;((S)-3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)((1s,3r)-3-hydroxy-3-methylcyclobutyl)methanone;1-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-2-methoxyethan-1-one;1-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-2-(dimethylamino)-2-methylpropan-1-one;1-(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidine-1-carbonyl)cyclopropane-1-carbonitrile;2-((3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)sulfonyl)ethan-1-ol;2-((3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)sulfonyl)-N,N-dimethylethan-1-amine;2-Methoxyethyl3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate;(3-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)((1s,3s)-3-methoxycyclobutyl)methanone;N-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclopentyl)-N-methylmethanesulfonamide;N-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclopentyl)-2-hydroxy-N-methylacetamide(Peak 1);(2S)—N-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclopentyl)-2-hydroxypropanamid;N-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclopentyl)-2-hydroxyacetamide;2-(1-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)phenyl)-3-azabicyclo[3.1.0]hexan-3-yl)ethan-1-ol;4-(3-(4-((1R,5S)-3-(2-Hydroxyethyl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile;1-((5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)methyl)piperidin-4-ol;5-((5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)methyl)-2-oxa-5-azabicyclo[2.2.1]heptane;4-(1-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)ethyl)morpholine;7-((5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine;4-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-1-(2-hydroxyethyl)piperidine-4-carbonitrile;4-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-1-(2-hydroxyacetyl)piperidine-4-carbonitrile;2-(3-(6-Methoxy-3-(6-(4-(2-methoxyethyl)piperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2-methylphenyl)acetonitrile;4-(6-Methoxy-3-(1-(1-(tetrahydro-2H-pyran-4-carbonyl)piperidin-4-yl-4-d)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile;4-(6-Methoxy-3-(1-((S)-1-(2-methoxyacetyl)pyrrolidin-3-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile;4-(6-Methoxy-3-(1-((S)-1-((S)-tetrahydrofuran-2-carbonyl)pyrrolidin-3-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile;(7R,8aS)-2-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol;N-(1-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-3-yl)-2-hydroxy-N-methylacetamide;(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-1-yl)(tetrahydrofuran-2-yl)methanone;(S)-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-1-yl)(1-methylpiperidin-2-yl)methanone;1-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-1-yl)-2-(dimethylamino)ethan-1-one;1-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-1-yl)-3-hydroxypropan-1-one;1-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-1-yl)-2-hydroxyethan-1-one;(S)-1-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-1-yl)-2-hydroxypropan-1-one;N-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclobutyl)-2-hydroxy-N-methylacetamide;1-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-1-yl-3-d)-2-hydroxyethan-1-one;Methyl4-(5-(5-(1-Cyano-2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidine-1-carboxylate;4-(6-Methoxy-3-(6-(1-(morpholine-4-carbonyl)piperidin-4-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile,Peak 2;4-(3-(6-(1-Acetylpiperidin-4-yl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile,Peak 2;4-(3-(6-(1-Acetylpyrrolidin-3-yl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile;4-(6-Methoxy-3-(6-(1-(morpholine-4-carbonyl)pyrrolidin-3-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile;4-(3-(1-(Cyanomethyl)-1H-pyrazol-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile;4-(6-Methoxy-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile;3-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-1-yl)propanenitrile;N-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclobutyl)-2-methoxy-N-methylacetamide;N-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclobutyl)-3-hydroxy-N-methylpropanamide;(S)—N-(3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclobutyl)-2-hydroxy-N-methylpropanamide;1-(1-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-hydroxyethan-1-one;(R)1-(1-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-hydroxyethan-1-one,two enantiomers;(S)1-(1-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-hydroxyethan-1-one,two enantiomers;(1-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)((R)-4-methylmorpholin-3-yl)methanone;5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-3-(6-(3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine2-(1-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)ethan-1-ol;(R)2-(1-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)ethan-1-ol,two enantiomers; (S)2-(1-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)ethan-1-ol,two enantiomers;3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-1-((R)-4-methylmorpholine-3-carbonyl)pyrrolidine-3-carbonitrile;(R)-4-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-1-(4-methylmorpholine-3-carbonyl)piperidine-4-carbonitrile;1-(1-(4-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-hydroxyethan-1-one;3-(5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-1-(2-hydroxyacetyl)pyrrolidine-3-carbonitrile;(S)-4-((5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)methyl)-1,3-dimethylpiperazin-2-one;and(1R,4R)-5-((5-(5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)methyl)-2-oxa-5-azabicyclo[2.2.1]heptane;or a pharmaceutically acceptable salt of any of the aforementioned. 52.A pharmaceutical composition comprising a compound of claim 1 or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier or excipient.
 53. A method of inhibiting an FGFR3enzyme comprising contacting said enzyme with a compound of claim 1 or apharmaceutically acceptable salt thereof.
 54. A method of treatingcancer in a patient comprising administering to said patient atherapeutically effective amount of a compound of claim 1 or apharmaceutically acceptable salt thereof.
 55. A method of treatingcancer in a patient comprising administering to said patient atherapeutically effective amount of a compound of claim 1 or apharmaceutically acceptable salt thereof in combination with anothertherapy or therapeutic agent.
 56. The method of claim 54, wherein saidcancer is selected from adenocarcinoma, bladder cancer, breast cancer,cervical cancer, cholangiocarcinoma, colorectal cancer, endometrialcancer, esophageal cancer, gall bladder cancer, gastric cancer, glioma,head and neck cancer, hepatocellular cancer, kidney cancer, livercancer, lung cancer, melanoma, ovarian cancer, pancreatic cancer,prostate cancer, rhabdomyosarcoma, skin cancer, thyroid cancer,leukemia, multiple myeloma, chronic lymphocytic lymphoma, adult T cellleukemia, B-cell lymphoma, acute myelogenous leukemia, Hodgkin's ornon-Hodgkin's lymphoma, Waldenstrom's Macroglubulinemia, hairy celllymphoma, and Burkett's lymphoma.
 57. The method of claim 54, whereinsaid cancer is selected from adenocarcinoma, bladder cancer, breastcancer, cervical cancer, cholangiocarcinoma, endometrial cancer, gastriccancer, glioma, head and neck cancer, lung cancer, ovarian cancer,leukemia, and multiple myeloma.
 58. A method for treating a skeletal orchondrocyte disorder in a patient comprising administering to saidpatient a therapeutically effective amount of a compound of claim 1 or apharmaceutically acceptable salt thereof.
 59. The method of claim 58,wherein said skeletal or chondrocyte disorder is selected fromachrondroplasia, hypochondroplasia, dwarfism, thanatophoric dysplasia(TD), Apert syndrome, Crouzon syndrome, Jackson-Weiss syndrome,Beare-Stevenson cutis gyrate syndrome, Pfeiffer syndrome, andcraniosynostosis syndrome.